Tsonga switched his rackets to Babolat (previously using Wilson) and started his 2010 season at the AAMI Kooyong Classic, after recovering from a wrist injury. After two wins and a walkover, he lost to Fernando Verdasco in the final. At the 2010 Australian Open, Tsonga beat Sergiy Stakhovsky, Taylor Dent, Tommy Haas, and Nicolás Almagro. In the quarterfinals, he beat world no. 3 Novak Djokovic, in his second five-set match. Tsonga's fatigue soon took a toll on him, however, as he was badly beaten in the semifinals by no. 1 Roger Federer.
Tsonga then entered Open 13 in Marseilles, France. He had two wins, but lost against Julien Benneteau in the semifinal, ending his title defense. Despite plans of not playing at the 2010 Dubai Tennis Championships, he accepted a wildcard and became the fifth seed in the tournament. He had a win against Michaël Llodra, who retired due to injury, but then struggled with form and lost to Ivan Ljubičić in the second round. The Davis Cup was next against Germany. In the singles, Tsonga helped France take an unassailable 3–0 lead, by winning the second-rubber match against Benjamin Becker, but was forced to retire against Simon Greul due to a recurring injury.
At the 2010 BNP Paribas Open, Tsonga lost to Robin Söderling in the fourth round. He was seeded eighth at the 2010 Sony Ericsson Open in Miami. He beat Guillermo García-López, Philipp Kohlschreiber, and 12th seed Juan Carlos Ferrero, before losing to second seed Rafael Nadal, after blowing eight break-point opportunities. Tsonga then made his debut at the 2010 Monte-Carlo Rolex Masters. He had a win over Nicolás Almagro, but was edged out in an exciting match against Juan Carlos Ferrero.
After nursing an injury, Tsonga entered the 2010 Barcelona Open Banco Sabadell. After wins over Jan Hájek and Nicolás Almagro, he was stunned by Dutch youngster Thiemo de Bakker in the quarterfinals. Tsonga made it all the way to the quarterfinals at the 2010 Internazionali BNL d'Italia, but was beaten by 13th seed David Ferrer. At the 2010 Mutua Madrileña Madrid Open, he was forced to retire in the opening round against Guillermo García-López.
Seeded eighth at the 2010 French Open, Tsonga defeated Daniel Brands, in five sets, Josselin Ouanna, and Thiemo de Bakker. Unfortunately, in the fourth round, Tsonga had to withdraw after losing the first set against Mikhail Youzhny, due to the progressive regional back pain from the previous round. Scans showed that Tsonga had sustained a right hip injury. In a tune-up event to Wimbledon, at the Boodles Challenge exhibition tournament, Tsonga had wins against Nikolay Davydenko and Philipp Kohlschreiber.
The All England Club was Tsonga's next stop, and he was seeded tenth. He had tough wins over Robert Kendrick and Alexandr Dolgopolov, before easier victories over Tobias Kamke and Julien Benneteau. However, in the quarterfinals, he eventually fell to home favorite Andy Murray in four sets. Not long after his Wimbledon campaign, Jo suffered a heavy knee injury. It caused him to withdraw from all the US Open Series events, including the US Open.
He made his return in October for his title defense at the 2010 Rakuten Japan Open Tennis Championships as the third seed, but rustiness was apparent, and he lost early to Jarkko Nieminen. Entering the 2010 Shanghai Rolex Masters 1000 as the 12th seed, Tsonga had wins over Feliciano López, Sam Querrey, and Florian Mayer, before losing in the quarterfinals in straight sets to eventual champion Andy Murray. He then entered the Kremlin Cup in Moscow, but lost against Viktor Troicki in the second round. A week later, Tsonga made a semifinal appearance at the Open Sud de France in Montpellier, but was beaten by Gaël Monfils for the first time.
During the week in Montpellier, Tsonga re-aggravated his knee problem. He missed the Paris Masters, as well as the important French Davis Cup final against Serbia. It was a tough end to the season for Tsonga, as he finished the season outside the top 10 for the first time in three years, compiled a 31–16 win-loss record (his worst tally since 2007), and failed to reach a single final during the season.