On April 7, 2010, Rentería had five hits (in five at-bats) in a 10–4 victory over Houston. He started the season well, as he was batting .320 through April 30. However, on April 30, he was forced to leave a game against Colorado after two innings with an injured groin. After missing four games, he returned to the lineup on May 6, but he left that game after two innings when he reinjured the groin. He was placed on the disabled list the next day. He was activated from the DL on May 22, but, after three games, he strained a hamstring on May 25 and was placed on the disabled list again the next day. He returned to the Giants on June 19. However, he returned to the disabled list on August 11 with a biceps injury received the previous night. He returned to the Giants on September 1, but Giants' manager Bruce Bochy announced that Juan Uribe, who had been playing well while substituting for Rentería at short, would remain the starting shortstop, which made Rentería a reserve player. He had four hits on September 16, in a 10–2 win over the Dodgers. On September 23, with the Giants trailing San Diego in the NL West, Rentería delivered a speech during a team meeting in which he told his teammates it could be his last year, and he wanted the Giants to make the playoffs. The Giants managed to overtake San Diego, and they did make the playoffs. Rentería finished the year with career-lows in games (72), hits (67), home runs (three, tied with his 1998 total), and RBI (22). During the season, he also began contemplating retirement.
In the 2010 NLCS against Philadelphia, Rentería reclaimed a starting role when he started four games (the Giants benched third baseman Pablo Sandoval and shifted Uribe to third base). He only had one hit in the series, but he scored the winning run in the Giants' 3–0 victory in Game 3, and he retained the starting job in the World Series. In Game 2 of the series, against the Texas Rangers, he broke a scoreless tie in the fifth inning when he homered off C. J. Wilson to give the Giants a 1–0 lead. He later added a two-run single in the eighth inning as the Giants won 9–0. Before Game 5, with the Giants leading the series 3–1, Rentería joked with teammate Andrés Torres that he was going to hit a home run. In the seventh inning, with runners at second and third, two outs, and no score, Rentería hit a three-run home run off Rangers' pitcher Cliff Lee that won the series for the Giants. The feat made him only the fourth player to have two series-winning hits in history, along with Yogi Berra, Joe DiMaggio, and Lou Gehrig. For his contributions, he was named the 2010 World Series Most Valuable Player, making him the first player from Colombia to achieve this feat. The Giants declined his option on November 5, but Rentería did announce that he planned to play in 2011. The Giants did offer him a one-year, one million dollar contract as a utility player, but Rentería declined.