After a decorated college career at the University of Tennessee, Chase Headley translated his success as a Volunteer into a highly regarded second-round pick by the San Diego Padres in the 2006 amateur draft. The switch-hitter showed advanced skills that helped him quickly progress through the minor leagues, earning a brief call-up to the majors late in the 2007 season. Although he started 2008 back in the minors, he made his way back to Southern California by June, quickly earning an everyday role in the lineup. Initially moved to left field to fit veteran roster needs, he eventually returned to his natural position at third base.

Headley’s early Padres career showed steady growth, culminating in a standout 2012 season. He hit a career-high 31 home runs, led the league with 115 RBIs, and posted a .279/.376/498 slash line with an .875 OPS. Despite a weak offense, he earned a Silver Slugger and finished fifth in MVP voting. His defense also improved, winning a Gold Glove in 2012, strengthening San Diego's infield.

After slipping back to his regular production in 2013, Headley was traded mid-year in 2014 to the Yankees.  New York would send him back after the 2017 Season, and Headley briefly returned to San Diego before he was released in May.

With the Padres, Headley contributed 87 home runs, 879 hits, and batted .263.