Cashner took a no-hitter into the sixth inning before Rajai Davis hit a one-out flare single into center field, just past the glove of outstretched second baseman Jedd Gyorko. Davis stole second and third, and Ian Kinsler walked before Miguel Cabrera hit into a double play.
Cashner ended his remarkable outing by striking out Cabrera on a 95-mph fastball.
Cashner (1-1) retired 14 in a row before allowing the single. He walked two.
The 6-foot-6 right-hander also threw a one-hitter in a 2-0 win at Pittsburgh on Sept. 16, facing the minimum 27 batters.
Dating to Aug. 19, Cashner has allowed two or fewer earned runs in nine straight starts for an ERA of 0.96.
The Padres hit Rick Porcello hard, collecting 10 hits in his 6 1-3 innings. He left after Cashner singled.
The Padres were onto Porcello from the start. Everth Cabrera hit a leadoff single, advanced on two groundouts and scored on Gyorko's triple. The ball hit the heel of right fielder Don Kelly's glove and hit the ground as Kelly slammed headfirst into the wall. After being checked by a trainer, Kelly stayed in the game.
Headley then doubled into the left-center gap to bring in Gyorko.
Headley homered to right on a 2-2 slider from Porcello with one out in the sixth, his first. It was estimated at 385 feet. Seth Smith was aboard on a leadoff double.
Porcello (1-1) allowed five runs and struck out five.