Hoffman went 4-5 with a 2.98 ERA and 42 saves in 49 save opportunities over 61 games with the Padres. In 57.1 innings he allowed 49 hits, walked 15 and struck out 44.

He became the first player in history to surpass 500 saves and ended the season with 524.

2006

Hoffman became the all-time saves leader on September 24, 2006 with his 479th career save to pass Lee Smith. He also won the Rolaids Relief Man of the Year Award, converting 46 of 51 attempts and was the Cy Young runner-up. He became the first pitcher to have at least 30 saves in 11 seasons.

Appearing in 65 games, the most since he made 70 appearances in 2000, Hoffman fashioned a 2.14 ERA across 63 innings. He walked only 13 while striking out 50, holding hitters to a .205 batting average.