The Padres invited Latos to spring training in 2009, but he suffered a minor ankle sprain that limited his appearances. Latos started the 2009 season in Fort Wayne and allowed only one run in four starts. He was then promoted to the San Antonio Missions of the Class AA Texas League. At San Antonio, Latos had a 5–1 win–loss record and threw five perfect innings in his last start for San Antonio on July 9. Between Fort Wayne and San Antonio, Latos had an 8–1 record, a 1.38 ERA, 73 strikeouts, and a .168 batting average against (BAA). The Padres named Latos their Padres Minor League Pitcher of the Month for May. Latos was selected to play in the 2009 All-Star Futures Game, and threw one scoreless inning.
The Padres promoted Latos to make his major league debut on July 19, 2009, against the Colorado Rockies. In his major league debut, Latos pitched four innings, allowing three hits and two runs while striking out four, while throwing 75 pitches. He recorded his first major league win on July 24. Latos became the first pitcher in Padres history to win four of his first five career starts. Latos made ten starts for the Padres in 2009, pitching to a 4–5 record and a 4.68 ERA.
However, Latos lost his last five starts of the 2010 season, culminating with a 3–0 loss to the San Francisco Giants on October 3 that, combined with an Atlanta Braves win, eliminated the Padres from playoff contention. The San Diego Union-Tribune attributed his struggles at the end of the year to fatigue, as his 189 ⁄3 innings for the season were 66 ⁄3 more than he pitched in 2009.