On November 11, 2015, the Yankees traded Pirela to the San Diego Padres for minor league pitcher Ronald Herrera.
He began the 2016 season with the El Paso Chihuahuas of the Class AAA Pacific Coast League, and was promoted to the Padres on April 22.
 Pirela played in 15 games with the Padres in 2016, making nine starts at second base and one in right field, before being optioned to El Paso when Yangervis Solarte was activated from the disabled list on May 21.
 Pirela was shut down in June with an Achilles tendon injury after playing in only 35 minor league games on the season.
 He had originally hurt the Achilles in the spring and it affected his performance all season.
 Pirela was non-tendered in the 2016 offseason, and became a free agent.
He signed a minor league contract with the Padres on December 13, 2016.

Pirela began the 2017 season with El Paso, where he batted .331/.387/.635 with 13 home runs in 181 at bats.
The Padres promoted Pirela to the Major Leagues on June 6.
 Pirela was slotted into left field and impressed with his bat, securing the number three spot in the batting order by August and holding onto the left field position after Opening Day left fielder Travis Jankowski came off the disabled list.
 Pirela saw his season ended in mid-September with a sprained finger, but he led the Padres regulars in batting average, on-base percentage, and slugging percentage, and was the Padres nominee for the Hank Aaron Award.
 He finished 2017 with a .288/.347/.490 batting line with 10 home runs and 40 RBIs in 83 games, playing 72 games in the outfield, 7 games at second base, 5 games at first base, and 1 game at third base.

Pirela began 2018 as a starter for the Padres, but he saw his playing time significantly shrink as the season progressed.
 He began the season as the regular left fielder, but took over second base from Carlos Asuaje in May as Franchy Cordero moved over to left.
 When Asuaje was recalled from El Paso on July 1 and moved back onto second base, Pirela had no regular position but continued to appear as a pinch hitter and utility player.
In 2018 with San Diego he batted .249/.300/.345 with 5 home runs and 32 RBIs in 146 games.

Pirela started the 2019 season in AAA but was recalled to the majors on April 19, 2019, before being placed on the injured list with an oblique strain five days later.
For El Paso he batted .353/.401/.674 with 18 home runs in 221 at bats.
He was designated for assignment on July 22.
On November 11, 2015, the Yankees traded Pirela to the San Diego Padres for minor league pitcher Ronald Herrera. He began the 2016 season with the El Paso Chihuahuas of the Class AAA Pacific Coast League, and was promoted to the Padres on April 22.  Pirela played in 15 games with the Padres in 2016, making nine starts at second base and one in right field, before being optioned to El Paso when Yangervis Solarte was activated from the disabled list on May 21.  Pirela was shut down in June with an Achilles tendon injury after playing in only 35 minor league games on the season.  He had originally hurt the Achilles in the spring and it affected his performance all season.  Pirela was non-tendered in the 2016 offseason, and became a free agent. He signed a minor league contract with the Padres on December 13, 2016.
Pirela began the 2017 season with El Paso, where he batted .331/.387/.635 with 13 home runs in 181 at bats. The Padres promoted Pirela to the Major Leagues on June 6.  Pirela was slotted into left field and impressed with his bat, securing the number three spot in the batting order by August and holding onto the left field position after Opening Day left fielder Travis Jankowski came off the disabled list.  Pirela saw his season ended in mid-September with a sprained finger, but he led the Padres regulars in batting average, on-base percentage, and slugging percentage, and was the Padres nominee for the Hank Aaron Award.  He finished 2017 with a .288/.347/.490 batting line with 10 home runs and 40 RBIs in 83 games, playing 72 games in the outfield, 7 games at second base, 5 games at first base, and 1 game at third base.
Pirela began 2018 as a starter for the Padres, but he saw his playing time significantly shrink as the season progressed.  He began the season as the regular left fielder, but took over second base from Carlos Asuaje in May as Franchy Cordero moved over to left.  When Asuaje was recalled from El Paso on July 1 and moved back onto second base, Pirela had no regular position but continued to appear as a pinch hitter and utility player. In 2018 with San Diego he batted .249/.300/.345 with 5 home runs and 32 RBIs in 146 games.
Pirela started the 2019 season in AAA but was recalled to the majors on April 19, 2019, before being placed on the injured list with an oblique strain five days later. For El Paso he batted .353/.401/.674 with 18 home runs in 221 at bats. He was designated for assignment on July 22.
José Pirela