As a junior in 2002, del Potro won the Orange Bowl 14s title, beating Marin Čilić en route to a victory over Pavel Tchekov in the final. In 2003, at the age of 14, del Potro received wild cards to three ITF Circuit events in Argentina, where he lost in straight sets in the first round of each.

In May 2004, del Potro won his first senior match, at the age of 15, at the ITF Circuit event in Buenos Aires by defeating Matias Niemiz. He then went on to lose in three sets to Sebastián Decoud in the second round. His next victory came over five months later against the Chilean Álvaro Loyola in a tournament in Antofagasta. Later that year, del Potro reached the quarterfinals of the ITF Circuit event in Campinas, Brazil; recording victories over Henrique Mello and Alessandro Camarco. Del Potro won two more matches before the end of the year and saw his world ranking rise from no. 1441 in August to no. 1077 in November. He also reached the finals in the Argentina Cup and Campionati Internazionali D’Italia Junior tournaments.

As a junior, del Potro reached as high as No. 3 in the combined junior world rankings in January 2005.

Del Potro reached his first final of the ITF Junior Circuit on 11 January 2005, the “Copa del Cafe (Coffee Bowl)” Junior ITF Tournament in Costa Rica, where he lost to Robin Haase in three sets. He was involved in a dispute with the umpire during this match, who decided to stop play because of rain, which del Potro believed favoured Haase. Because of the rain delays, the final set had to be played indoors; this was the first time the indoor courts had been used in the 44-year history of the youth tournament.

Del Potro qualified for the main draw of his first Grand Slam in the 2006 French Open at the age of 17. He lost in the opening round to former French Open champion and 24th seed Juan Carlos Ferrero. Having received a wild card, he reached the quarterfinals of the ATP event in Umag, Croatia, where he lost in three sets to the eventual champion, Stanislas Wawrinka. In Spain, he participated in the Open Castilla y León Challenger tournament held in Segovia, defeating top seed Fernando Verdasco in the quarterfinals and Benjamin Becker in the final.

Del Potro qualified for his first US Open in 2006, after being seeded ninth in the qualifying stages, where he beat Brian Vahaly, Wayne Arthurs, and Daniel Köllerer in straight sets. In the US Open, he lost in the first round to fellow qualifier Alejandro Falla of Colombia in four sets. He went on to qualify for his first ATP Masters Series tournament in Spain, the Mutua Madrileña Madrid Open, where he lost in the first round to Joachim Johansson. After receiving a wild card thanks to Roger Federer, he reached the quarterfinals of the 2006 Davidoff Swiss Indoors in Basel, Switzerland; defeating lucky loser Tobias Clemens in the first round and George Bastl in the second round, before losing to the eventual runner-up Fernando González in three sets. Del Potro finished 2006 as the youngest player in the top 100 at 18 years, 2 months.

At the 2008 US Open, del Potro progressed to the third round, where he won his first match to five sets in the circuit against Gilles Simon to reach the round of 16. He went on to defeat Japanese teenager Kei Nishikori in straight sets. In the quarterfinals, he was stopped by eventual finalist Murray, losing after almost four hours. The defeat came after 23 consecutive victories: the second-longest winning streak in 2008 and the longest winning streak by a player outside the top 10 in the last 20 years.

At the 2009 Wimbledon Championships, his poor grass-court form from the past continued, as he went down to unseeded Lleyton Hewitt in the second round. In the Davis Cup quarter-final against the Czech Republic, del Potro won his matches against Ivo Minář and Berdych in straight sets, but Argentina still lost the tie 2–3, eliminating them from the competition. A few weeks later, he defeated Hewitt and Fernando González en route to the Washington final. He successfully defended his title against top-seeded Wimbledon finalist Andy Roddick to win his second tournament of the year and become the first player since Andre Agassi to win back-to-back Washington titles. Del Potro played the following week at the Masters 1000 in Montreal, where he was seeded sixth, defeating world No. 2 Nadal in the quarterfinals, his second win in a row over Nadal. He then defeated Roddick in the semifinals, saving a match point, to advance to his first Masters 1000 final, and to improve his head-to-head record against Roddick to 3–0. In the final, he lost against Murray in three sets. He later withdrew from the next Masters 1000 event in Cincinnati due to fatigue.

In the quarterfinals he defeated Roger Federer in four tight sets; his second victory over the Swiss at the US Open, having beaten him in the final in 2009. By doing so he reached his first major semifinal since Wimbledon 2013. His run came to an end in 4 sets, losing to World No. 1 Rafael Nadal.

Del Potro has a 3–7 (30.0%) record against Andy Murray. They only played two finals. The first was in the 2009 Rogers Cup, which was won by Murray. However, when del Potro beat Murray in the quarterfinals of the 2013 BNP Paribas Open, del Potro won against all members of the Big Four in 2013. In their second final, del Potro lost to Murray in the 2016 Summer Olympics. However, during Argentina’s Davis Cup semi-final tie against Great Britain, del Potro got revenge by beating Andy Murray in a five set thriller that was both men’s longest match of their careers.

He went on to play in Rotterdam at the 2012 ABN AMRO World Tennis Tournament in Rotterdam, where he was third seed. Here he defeated Tomáš Berdych in order to make it to his first final of an ATP 500 level tournament or higher after returning from his wrist injury in 2010. He lost to Federer in straight sets in the final. At the Open 13 in Marseille, del Potro defeated Davydenko, Gasquet, Tsonga, and Michaël Llodra in the final to get his tenth ATP championship. Del Potro then had a good run in Dubai, reaching the semifinals, then losing to Roger Federer again in straight sets. Del Potro lost in the quarterfinals of the BNP Paribas Open to Federer for the fourth time that year. He made it to the fourth round of the Sony Ericsson Open, but lost to David Ferrer in two sets.

On grass, del Potro began at the 2013 Aegon Championships, where he won his first comeback match in three sets against Xavier Malisse, who had achieved his biggest win at the Queens Club against Novak Djokovic in 2010. Del Potro came back from behind in the third set to take the match. He defeated Daniel Evans, only to be upset on the quarterfinals by Lleyton Hewitt

Del Potro used the Wilson Hyper ProStaff 6.1 Midplus Stretch early on in his career, and has continued to use this racquet under new paint jobs years later. Del Potro is very superstitious, and after suffering a wrist injury shortly after switching to the Wilson BLX Pro Tour paint job in 2010, he returned to playing with the then outdated Wilson K-Factor 6.1 95 paint job. He particularly favored the exact racquets he had used to win his only Grand Slam title at the 2009 US Open. He again refused to update his racquet to the Wilson BLX Juice Pro in 2012, and in 2014 had only a few K-Factor racquets left. For strings, he uses Luxilon ALU Power strung at 58 lbs. He currently makes use of the Wilson ProStaff 97.

After the Australian Open, he participated in the 2011 SAP Open in San Jose, where he was accepted into the main draw via protected ranking (PR). He reached the semifinals without dropping a set, however he lost to top seed Fernando Verdasco in straight sets. Del Potro’s next scheduled tournament was the 2011 Regions Morgan Keegan Championships and the Cellular South Cup, where he was accepted into the main draw via wildcard. Here, he made his second consecutive ATP semifinal, where he lost to top seed, world No. 8, and eventual champion Andy Roddick. To continue preparing for his first ATP Masters event since 2009, del Potro entered the 2011 Delray Beach International Tennis Championships. He defeated Ričardas Berankis, Teymuraz Gabashvili, Kevin Anderson and second seed Mardy Fish, to advance to an ATP-level final stage of a tournament since 2009 at the Barclays World Tour Finals in London. In the final, he defeated an erratic Janko Tipsarević in two sets to get back in the winners circle.

He then played in 2011 Estoril Open, which was del Potro’s first tournament on clay since he lost the 2009 Roland Garros semifinal to the eventual champion Roger Federer. In Estoril, he defeated Fernando Verdasco in the final. On the way to the final, del Potro defeated top seeded Robin Söderling (Who was two time-finalist in the French Open) and dropped just one set in his five matches. After suffering an 8-millimeter tear in his left rectus, del Potro withdrew from 2011 Mutua Madrid Open and did not participate in the 2011 Internazionali BNL d’Italia, but confirmed that he would play the French Open. Del Potro lost to Novak Djokovic in the third round.

At the 2011 Rogers Cup, seeded 16th, del Potro defeated Jarkko Nieminen before losing to Marin Čilić in the second round. At the Western & Southern Masters tournament, del Potro lost to Roger Federer, snapping the two-match winning streak he had against his rival. Del Potro entered the 2011 US Open seeded 18th. He beat Filippo Volandri and Diego Junqueira before losing to Gilles Simon in the third round, thus ending his US Open campaign.

Del Potro has a 6–11 (35.3%) record against Rafael Nadal. Del Potro bested Nadal in the semifinals en route to his 2009 US Open title which was the first time a player managed to beat both Roger Federer and Nadal in the same Grand Slam tournament (Novak Djokovic did this at the US Open 2011). However the Spaniard managed to win both times in the Indian Wells Masters encounters, in the 2011 semifinal and the 2013 final. Nadal also won the fourth and last rubber of the 2011 Davis Cup final against the Argentine. Del Potro gained the upper hand at the 2013 Shanghai Masters, defeating Nadal to reach the final where he lost to Djokovic. Del Potro defeated Nadal in a third set tiebreak in the semifinal of the 2016 Olympics in Rio de Janeiro, while Nadal stopped Del Potro’s 2017 US Open run, defeating him in a 4-set semifinal. In the quarterfinals of 2018 Wimbledon, Nadal came from two sets to one down to defeat Del Potro in an epic five-set match. In their most recent meeting, Del Potro advanced to the final of the US Open when Nadal had to retire, while trailing by two sets to love.

At the 2013 Japan Open, Del Potro beat Marcos Baghdatis, Carlos Berlocq, Alexandr Dolgopolov, and Nicolas Almagro before beating third seed Milos Raonic to win his third title of the year.

In October, Del Potro reached the final of the 2013 Shanghai Rolex Masters, defeating Philipp Kohlschreiber, Tommy Haas, Nicolás Almagro, and Rafael Nadal (for the first time since the semifinals of the 2009 US Open) en route, but eventually losing to defending champion Novak Djokovic in a third-set tiebreak. Later, he beat Roger Federer at the 2013 Swiss Indoors in the final, his fourth title of the year. However, lost to Federer at the 2013 BNP Paribas Masters and in a winner-take-all, round-robin clash in the 2013 ATP World Tour Finals. He finished the year with a 51–16 record, winning four titles overall and $4,294,039. Del Potro was named Argentina’s Sportsman of the Year.

Del Potro has a 4–16 (20.0%) record against Novak Djokovic. Djokovic won their first four meetings, before back to back victories for del Potro at the 2011 Davis Cup and their Bronze medal match at the 2012 Summer Olympics in straight sets. However, in 2013, Djokovic got the upper hand on the rivalry again and won two of the most important matches between them to date; an epic five-setter at the 2013 Wimbledon Championships semifinals and a thrilling three-setter at the 2013 Shanghai Masters final. In the same year, del Potro defeated Djokovic en route to his second Masters 1000 final, at the 2013 Indian Wells Masters, where he lost to Nadal. Del Potro upset Djokovic in the first round at the 2016 Olympics in Rio en route to the final, where he lost to Murray. Djokovic defeated Del Potro in three close sets in the final of the 2018 US Open, which was the first grand slam final for Del Potro since his victory at the 2009 US Open. Three of his four victories have come via national representation tournaments.

In February, at the 2014 Rotterdam Open, he eased past Gaël Monfils and Paul-Henri Mathieu in straight sets, but fell to Latvian Ernests Gulbis in the quarterfinals. In the 2014 Dubai Tennis Championships, he retired against Somdev Devvarman after losing the first set due to his wrist injury. The same injury led to his subsequent withdrawal from Masters 1000 series events in Indian Wells and Miami, meaning that del Potro dropped to world No. 8.

Del Potro began his 2015 season with wrist pain and was not sure whether he would play Sydney and the Australian Open. However, at the last minute he decided to play both tournaments. He had not played a tournament since February 2014, but he started the 2015 Apia International Sydney with a straight-sets win against Sergiy Stakhovsky. In the second round, his opponent was world No. 19 and top seed Fabio Fognini. It was a tough test for del Potro, but he proved to be stronger than the Italian. Del Potro was through to the quarterfinals, but lost to Mikhail Kukushkin in two tiebreakers. After his Sydney campaign, he was drawn to play Jerzy Janowicz in the first round of the 2015 Australian Open, del Potro withdrew due to his wrist injury the day before the match started. Del Potro played in Miami and was not seen for nearly a year, undergoing surgery again in June 2015.

He played his first tournament since undergoing wrist surgery in the 2016 Delray Beach Open. In his first competitive match in almost a year, del Potro defeated Denis Kudla in two sets. He followed this up with a straight sets win over Australian John-Patrick Smith. He defeated Jérémy Chardy in two sets in the quarterfinal, reaching his first semifinal since 2014; which he lost to eventual champion Sam Querrey. He returned to Indian Wells, competing in the first round, winning against Tim Smyczek in two sets. He lost in the next round to Tomas Berdych in straight sets. His next tournament was the Miami Open. He won his first match against countryman Guido Pella in two sets. He was set to play Roger Federer for the first time in more than two years, but just hours before the match Federer withdrew due to a stomach virus. He then played lucky loser and countryman Horacio Zeballos and lost in straight sets. He then competed in his first clay-court tournament since 2013 at the BMW Open. He won his first clay-court match in three years against Dustin Brown, beating him in two sets.

In the 2016 Olympic Games, del Potro defeated top seed and world no. 1 Novak Djokovic in the first round. It was a huge win for him because he was ranked no. 145 in the world and was coming back from a bad injury. He also defeated João Sousa and Taro Daniel in three sets. Next, he defeated top-20 player Roberto Bautista Agut to guarantee a medal match. He played 2008 gold medalist and the 2016 doubles gold medalist, Rafael Nadal. He defeated him in three tight sets to guarantee a medal. Del Potro played in his first gold medal match against the reigning Wimbledon champion from the previous month, Andy Murray. He lost in four grueling sets in over four hours. However, del Potro said after beating Nadal “I already won silver, that’s good enough for me.”

After the Olympics, del Potro was granted a wild card to the US Open. He was drawn against countryman Diego Schwartzman and defeated him in straight sets. In the second round, he faced and defeated 19th seed and top-ranked American Steve Johnson in straight sets, fighting back from down a break during both the first and second sets. In the third round, he faced 11th seed and Grand Slam finalist David Ferrer, and again defeated him in straight sets. In the fourth round, he faced 8th seed Dominic Thiem. After del Potro won the first set, the match ended when Thiem retired during the second set. Del Potro then lost to eventual champion Stan Wawrinka in the quarterfinals in four sets. Del Potro then played against Murray in a rematch of the Olympic final in the Davis Cup. Del Potro won the thrilling 5-set match in 5 hours and 7 minutes. In his next tournament, del Potro played in the 2016 Shanghai Rolex Masters, where he was drawn to play 11th seed David Goffin. Despite being a set and a break up, del Potro eventually lost the match. After this, del Potro was given a wild card into the Stockholm Open. Del Potro beat John Isner, Nicolas Almagro, Ivo Karlovic, and Grigor Dimitrov on his way to the final. In the final, del Potro cruised to victory over Jack Sock to win his first title since his return from injury. Del Potro then played at the 2016 Swiss Indoors, where he comfortably beat qualifier Robin Haase in the first round. He then got revenge on Goffin in a straight sets win, before falling in 2 tight sets to Kei Nishikori in the quarterfinals.

Vying for Argentina’s first title, del Potro played in the 2016 Davis Cup against Croatia. His first match was a four set victory against Ivo Karlović. Partnering Leonardo Mayer, del Potro lost in doubles against Ivan Dodig and Marin Cilic. 2–1 down in matches, del Potro played in singles against Cilic, coming back from 2 sets down for the first time in his career to win in five sets. Described as one of the best Davis Cup comebacks ever, del Potro levelled the score at 2–2, paving the way for Federico Delbonis to complete the comeback by beating Ivo Karlović in straight sets, thus claiming Argentina’s first ever Davis Cup title.

Although he possessed a very consistent and powerful double-handed backhand, injury and surgeries on his wrist have rendered his backhand the main weakness in his game. Since his return in 2016, del Potro made tactical changes in his game in order to protect his wrist, like significantly reducing the pace of his two-hander and adopting a one-handed slice. Despite del Potro admitting that relying on slices is “not my game,” the shot has been effective in moving his opponents out of position and slowing down rallies enough to allow him to set up powerful offensive shots with his forehand. Furthermore, to compensate for the newfound vulnerability in his backhand wing, del Potro has improved the power and accuracy of his other shots, most notably his serve.

Del Potro withdrew from the Madrid Open, reappearing at the Italian Open where he reached the quarterfinals of a Masters 1000 tournament for the first time since the 2013 Paris Masters, following victories over 10th seed Grigor Dimitrov, Kyle Edmund and 7th seed Kei Nishikori, which was his first victory in 2017 over a top 10 ranked player. However, he succumbed yet again to world No. 2 Novak Djokovic in straight sets.

Del Potro has a 7–18 (28.0%) record against Roger Federer. They have met in 6 finals, all at ATP World Tour 500 Series level or higher, with del Potro leading 4–2; besides the US Open title he also captured both 2012 and 2013 Swiss Indoors finals and the 2018 Indian Wells final, while Federer has won finals against del Potro at the 2012 Rotterdam Open and the 2017 Basel Open. Del Potro also won their biggest match to date in 5 sets at the 2009 US Open final, shortly after Federer won their next most important match in 5 sets at the 2009 French Open semifinals a few months before. Federer also won the longest best of 3-set match in the history at the 2012 Olympic semifinal against del Potro, 19–17 in the deciding set. Del Potro also prevailed in 2017 US Open quarterfinals against Federer in 4 sets. Federer prevailed in three sets in the 2017 Basel final. However, at their most recent meeting at Indian Wells Masters in 2018, Del Potro won in the finals, winning his first Masters 1000.