The Padres started the season 20–41, the worst record in the major leagues at the time. By June 20, they were 22 games under .500.
Starting pitcher Casey Kelly, obtained in the 2010 trade of Adrian Gonzalez to the Boston Red Sox, made his major league debut with San Diego on August 27, 2012. Kelly earned a win after pitching six shutout innings in a 3–0 victory over the Atlanta Braves. He also recorded his first major league hit in the game. Kelly was the 15th different starting pitcher used by the Padres in 2012, which matched a club record set in 2002 and tied in 2009. The Padres ended the season with 24 pitchers throwing at least 15 innings.
Third baseman Chase Headley was rumored to be traded but was kept at the trade deadline in July. He was named the National League Player of the Week for the week ending August 12. He was later named National League Player of the Month for August, becoming the first Padre to be so honored since Tony Gwynn won the award in May 1997. Headley that month was tied for the major league lead in home runs (10) and led the majors with 31 RBIs. He hit .306 (33-for-108) in August with 20 runs scored and a .611 slugging percentage. He earned a second consecutive Player of the Month honor in September after hitting .324 that month with nine homers, 30 RBIs, a .410 on-base percentage, and a .645 slugging percentage. He was the second Padre to win Player of the Month in consecutive months, the first being third baseman Ken Caminiti in August and September of 1996. He became the first Padre to ever have more than one 30-RBI month. Over the final 57 games of the season, he batted .313 with 19 homers, 44 runs scored and 63 RBIs.
The Padres went 5–10 over their last 15 games, losing five consecutive series by 2–1 margins. However, San Diego was 42–33 after the All-Star break. They finished the season with a 76–86 record for a five-game improvement from 2011.
Headley led the NL in RBIs with 115, joining former Padre and Hall of Fame outfielder Dave Winfield (118 in 1979) as the only Padres to lead the league in RBIs. Headley set career highs in hits (173), runs (95), home runs (31), walks (86), RBIs, total bases (301), on-base percentage (.376) and slugging percentage (.498) and matched career highs in games played (161), doubles (31) and steals (17). He reached base in 146 games, breaking the Padres record held by Gwynn (144 in 1987). Shortstop Everth Cabrera became the first Padre to lead the NL in stolen bases with 44. He set a team record with a 91.7 percent success rate on steals (44-for-48), which also led the NL.
Headley was unanimously voted the Padre Player of the Year by writers covering the team, and Clayton Richard was the unanimous pick as the Padres Pitcher of the Year. Headley also won a Gold Glove Award after leading all major league third basemen in games played (159) and assists (315) and the NL in total chances (425).