Nadal began the year by participating in the Capitala World Tennis Championship in Abu Dhabi, United Arab Emirates. He defeated compatriot David Ferrer 7–6(3), 6–3 to reach his second final in the exhibition tournament. In the final, Nadal defeated Robin Söderling 7–6(3), 7–5.
Nadal participated in an Australian Open warm-up tournament, the Qatar ExxonMobil Open ATP 250 event in Doha, where he lost in the finals. He defeated Simone Bolelli of Italy 6–3, 6–3 in the first round, and in the second round, Nadal defeated Potito Starace 6–2, 6–2. Nadal's progress continued in the quarterfinals when he was up 6–1, 2–0 against Steve Darcis of Belgium, who eventually retired from the match. He defeated fifth seed Viktor Troicki 6–1, 6–3, winning 11 straight games in the semifinals. Nadal lost to Nikolay Davydenko 6–0, 6–7(8), 4–6 in the finals, despite dominating in the opening set and holding two match points in the second set. Davydenko also defeated Roger Federer in the semifinals before advancing to the finals.
In the first round of the Australian Open, Nadal defeated Peter Luczak of Australia 7–6(0), 6–1, 6–4. In the second round, he beat Lukáš Lacko 6–2, 6–2, 6–2. In the third round, he was tested by Philipp Kohlschreiber, finally beating him 6–4, 6–2, 2–6, 7–5. In the fourth round, he beat Ivo Karlović of Croatia, 6–4, 4–6, 6–4, 6–4. In the quarterfinals, Nadal pulled out at 3–0 down in the third set against Andy Murray, having lost the first two sets 6–3, 7–6(2). After examining Nadal's knees, doctors told him that he should take two weeks of rest, and then two weeks of rehabilitation.
Nadal reached the semifinals in singles at the BNP Paribas Open in Indian Wells, where he was the defending champion; however, eventual champion Ivan Ljubičić defeated him in three sets. He and countryman López won the doubles title, though, as wildcard entrants against number one seeds Daniel Nestor and Nenad Zimonjić. This boosted his doubles ranking 175 places to world number 66, whereas he was 241st before Indian Wells. After Indian Wells, Nadal reached the semifinals of the Sony Ericsson Open, where he lost to eventual champion Andy Roddick in three sets.
Nadal reached the final of the Monte-Carlo Rolex Masters in Monaco, after beating fellow Spaniard David Ferrer 6–3, 6–2 in the semifinals. This was Nadal's first tour final since Doha earlier in the year. He won the final 6–0, 6–1 over his compatriot Fernando Verdasco. He lost 14 games throughout all five matches, the fewest he had ever lost en route to a championship, and the final was the shortest Masters 1000 final in terms of games. With this win, Nadal became the first player in the open era to win a tournament title for six straight years.
Unlike in previous years, Nadal next chose to skip the Barcelona tournament (despite being that event's five-time defending champion), and his next tournament was the 2010 Internazionali BNL d'Italia. He defeated Philipp Kohlschreiber, Victor Hănescu, and Stanlias Wawrinka, all in straight sets, to win his 57th straight match in April. In the semis, he faced a resilient Ernests Gulbis, who defeated Roger Federer earlier in the tournament and took Nadal to three sets for the first time this clay-court season. Nadal eventually prevailed with a 6–4, 3–6, 6–4 in 2 hours and 40minutes. He then defeated compatriot David Ferrer in the final 7–5, 6–2 for his fifth title at Rome to equal Andre Agassi's record of winning 17 ATP Masters titles.
Nadal then entered the 2010 Mutua Madrileña Madrid Open, where he had finished runner-up the previous year. Being one of the top eight seeds, he received a bye in the first round. In the second round, he defeated qualifier Oleksandr Dolgopolov Jr in straight sets. He then played the six-foot-nine-inch American John Isner. Nadal comfortably came through in straight sets, 7–5, 6–4. He defeated Gaël Monfils in the quarterfinals 6–1, 6–3 and his countryman Nicolás Almagro in the next round, who was playing in his first Masters 1000 semifinal, 4–6, 6–2, 6–2. The first set of his match against Almagro would be just the second set he lost on clay up to this point in 2010. Nadal then defeated longtime rival Roger Federer 6–4, 7–6(5), avenging his 2009 finals loss to Federer. The win gave him his 18th Masters title, breaking the all-time record. He became the first player to win all three clay-court Masters titles in a single year and the first player to win three consecutive Masters events. Nadal moved back to No. 2 the following day.
Entering the French Open, many were expecting another Nadal-Federer final. However, this became impossible when rival Robin Söderling defeated Federer 3–6, 6–3, 7–5, 6–4 in the quarterfinals. The failure of Federer to reach the semifinals allowed Nadal to regain the world No. 1 ranking if he were to win the tournament. Nadal advanced to the final and defeated Soderling 6–4, 6–2, 6–4 to win the French Open. The win gave Nadal his seventh Grand Slam, tying him with John McEnroe, John Newcombe, and Mats Wilander on the all-time list, and allowed Nadal to reclaim the position of world No. 1, denying his biggest rival Roger Federer the all-time record for weeks at No. 1. By this win, Nadal became the first man to win the three Masters series on clay and the French Open. This was dubbed by the media as the "Clay Slam". This victory at Roland Garros marked the second time (2008) that Nadal had won the French Open without dropping a single set (tying the record held by Björn Borg). With the win in Paris he also booked his place at the World Tour Finals in London and became the first player to win five French Open titles in six years.
In June, Nadal entered the AEGON Championships, which he had won in 2008, at the prestigious Queen's Club. He played singles and doubles at this grass court tournament as a warmup for Wimbledon. Being one of the top eight seeds, he received a bye in the first round. In the second round, where he played his first match on grass since winning Wimbledon 2008, he defeated Marcos Daniel easily, 6–2, 6–2. In the third round, he played Denis Istomin of Uzbekistan, whom he defeated 7–6(4), 4–6, 6–4, to advance to the quarterfinals. However, he was defeated by compatriot Feliciano López 6–7(5), 4–6.
At the Wimbledon, Nadal beat Kei Nishikori 6–2, 6–4, 6–4. Nadal was taken to the limit by Robin Haase winning 5–7, 6–2, 3–6, 6–0, 6–3. He defeated Philipp Petzschner in the third round. The match was a 5-set thriller, with Nadal triumphing 6–4, 4–6, 6–7, 6–2, 6–3. During his match with Petzschener, Nadal was warned twice for receiving coaching from his coach and uncle, Toni Nadal, resulting in a $2000 fine by Wimbledon officials. Allegedly, encouraging words for Nadal shouted during the match were some sort of coaching code signal. He met Paul-Henri Mathieu of France in the round of 16 and comfortably beat Mathieu 6–4, 6–2, 6–2. In the quarterfinals, he got past Robin Söderling of Sweden in four sets 3–6, 6–3, 7–6(7–4), 6–1. He defeated Andy Murray in straight sets 6–4, 7–6(8–6), 6–4 to reach his fourth Wimbledon final.
Nadal won the 2010 Wimbledon men's title by defeating Tomáš Berdych in straight sets 6–3, 7–5, 6–4. After the win, Nadal said "it is more than a dream for me" and thanked the crowd for being both kind and supportive to him and his adversary during the match and in the semifinal against Andy Murray. The win gave him a second Wimbledon title and an eighth career major title just past the age of 24. The win also gave Nadal his first "Old World Triple"; the last person to achieve this was Björn Borg in 1978 ("Old World Triple" is a term given to winning the Italian Open, French Open, and Wimbledon in the same year).
In his first hard-court tournament since Wimbledon, Nadal advanced to the semifinals of the Rogers Cup, along with No. 2 Novak Djokovic, No. 3 Roger Federer, and No. 4 Andy Murray, after coming back from a one-set deficit to defeat Philipp Kohlschreiber of Germany, 3–6, 6–3, 6–4. In the semifinal, defending champion Murray defeated Nadal 6–3, 6–4, becoming the only player to triumph over the Spaniard twice in 2010. Nadal also competed in the doubles with Djokovic in a one-time, high-profile partnership of the world No. 1 and No. 2, the first such team since the Jimmy Connors and Arthur Ashe team in 1976. However, Nadal and Djokovic lost in the first round to Canadians Milos Raonic and Vasek Pospisil. The next week, Nadal was the top seed at the Cincinnati Masters, losing in the quarterfinals to 2006 Australian Open finalist Marcos Baghdatis.
At the 2010 US Open, Nadal was the top seed for the second time in three years. He defeated Teymuraz Gabashvili, Denis Istomin, Gilles Simon, number 23 seed Feliciano López, number 8 seed Fernando Verdasco, and number 12 seed Mikhail Youzhny all without dropping a set, to reach his first US Open final, becoming only the eighth man in the Open Era to reach the final of all four majors, and at age 24 the second youngest ever to do so, behind only Jim Courier. In the final, he defeated Novak Djokovic 6–4, 5–7, 6–4, 6–2 which completed the Career Grand Slam for Nadal and he became the second male after Andre Agassi to complete a Career Golden Slam. Nadal also became the first man to win grand slams on clay, grass, and hard court in the same year, and the first to win the French Open, Wimbledon, and the US Open in the same year since Rod Laver in 1969. Nadal and Mats Wilander are the only male players to win at least two Grand Slams each on clay, grass, and hardcourts in their careers. Nadal also became the first left-handed man to win the US Open since John McEnroe in 1984. Nadal's victory also clinched the year-end No. 1 ranking for 2010, making Nadal only the third player (after Ivan Lendl in 1989 and Roger Federer in 2009) to regain the year-end number one ranking after having lost it.
Nadal began his Asian tour at the 2010 PTT Thailand Open in Bangkok where he reached the semifinals, losing to compatriot Guillermo García López. Nadal was able to regroup, and at the 2010 Rakuten Japan Open Tennis Championships in Tokyo (debut), he defeated Santiago Giraldo, Milos Raonic, and Dmitry Tursunov. In the semifinals against Viktor Troicki, Nadal saved two match points in the deciding set tiebreaker to win it 9-7 in the end. In the final, Nadal comfortably defeated Gaël Monfils 6-1, 7-5 for his seventh title of the season.
Nadal next played in the 2010 Shanghai Rolex Masters in Shanghai, where he was the top seed, but lost to world No. 12 Jürgen Melzer in the third round, snapping his record streak of 21 consecutive Masters quarterfinals. On the 5th of November, Nadal announced that he was pulling out of the Paris Masters due to tendinitis in his left shoulder. On 21 November 2010, in London, Nadal won the Stefan Edberg Sportsmanship Award for the first time.
At the 2010 ATP World Tour Finals in London, Nadal defeated Roddick 3-6, 7-6(5), 6-4 in the first match, Djokovic 7–5, 6–2 in the second match, and Berdych 7-6(3), 6-1 in the third match, to advance to the semifinals for the third time in his career. This is the first time that Nadal achieved three wins in the round-robin stage. In the semifinal, he defeated Murray 7-6(5), 3-6, 7-6(6) in a hard-fought match to reach his first final at the tournament. In only their second meeting of the year, Federer beat Nadal in the final by a score of 6–3, 3–6, 6–1. After the match, Nadal stated: "Roger is probably the more complete player of the world. I'm not going to say I lost that match because I was tired." This was a reference to his marathon victory over Murray on Saturday. "I tried my best this afternoon, but Roger was simply better than me."
Nadal ended the 2010 season having won three Slams and three Masters 1000 tournaments, and having regained the No. 1 ranking.
Next up for Nadal was a two-match exhibition against Federer for the Roger Federer Foundation. The first match took place in Zürich on December 21, 2010, and the second in Madrid the next day.