On May 4, 2010, he was promoted to the Syracuse Chiefs of the Class AAA International League. In his first game with the Chiefs, he pitched six scoreless innings, striking out six batters while allowing one hit and one walk. That game drew 13,766 fans—the highest attendance in the 135-year history of baseball in Syracuse. In his second start, Strasburg was removed after pitching six no-hit innings. He finished his minor league stint with an overall record of 7–2, an ERA of 1.30, 65 strikeouts and 13 walks in 55 ⁄3 innings, and a walks plus hits per inning pitched (WHIP) ratio of 0.80.
Strasburg made his major-league debut on June 8, 2010, against the Pittsburgh Pirates. A Sports Illustrated columnist termed it "the most hyped pitching debut the game has ever seen". An ESPN article revealed the colloquial name for Strasburg's celebrated debut as "Strasmas". Strasburg picked up the win in his debut, pitching seven innings, allowing two earned runs and no walks and 14 strikeouts, setting a new team strikeout record that was previously held by John Patterson (13, twice). Also, he was the first pitcher in history to strike out at least eleven batters without issuing any walks in his pro debut, while falling just one strikeout short of the all-time record for a pitcher's debut—Karl Spooner (1954) and J. R. Richard (1971) both struck out 15, but each took nine innings to do it, and each walked three. (Bob Feller also struck out 15 in his first start, although it wasn't his big league debut). He struck out every batter in the Pirates' lineup at least once and struck out the last seven batters he faced—also a Nationals record. He threw 34 of his 94 pitches at 98 miles per hour (158 km/h) or faster, including two that reached 100 miles per hour (160 km/h).
In the 2010 season Strasburg pitched in 12 games, all starts, throwing 68 innings, 92 strikeouts and compiling a 2.91 ERA. He was named a pitcher on the 2010 Topps Major League Rookie All-Star Team.
Strasburg was placed on the disabled list with an inflamed right shoulder in July 2010. He returned to action on August 10, but in his third game back, on August 21, he was removed with an apparent injury. On August 27, the Nationals announced that Strasburg had a torn ulnar collateral ligament, requiring Tommy John surgery, and about 12 to 18 months of rehabilitation.
Strasburg's repertoire features five pitches: a four-seam fastball, his primary pitch at 95–97 miles per hour (153–156 km/h), which was recorded as high as 100 mph early in his career, and for which in the 2010 season was one of only three starting pitchers to have pitches of over 100 mph, and all did so at least 21 times (Justin Verlander and Ubaldo Jimenez); a two-seam fastball at 94–95 miles per hour (151–153 km/h); a curveball that Strasburg himself refers to as a slurve at 80–83 miles per hour (129–134 km/h); a changeup at 87–90 miles per hour (140–145 km/h). and a hybrid pitch he began using regularly in the 2016 season that his catcher Wilson Ramos described as a "slider-cutter," which moves laterally at 87–91 miles per hour (140–146 km/h). Strasburg throws a mix of all his pitches to left-handed hitters, but he mostly eliminates the changeup when facing right-handed hitters. He is liable to throw his four-seamer or slurve to right-handers with two strikes, and adds the changeup in those counts against lefties.
His velocity was not significantly affected by his Tommy John surgery in 2010. He had the fastest four-seam fastball among starting pitchers in the 2012 season, averaging 96.5 miles per hour (155 km/h). However, he had only one pitch in the seven seasons since Tommy John surgery to top over 100 mph.
On January 9, 2010, he married Rachel Lackey. They met as students at San Diego State. As of 2019, the couple has two daughters. The Strasburgs relocated full-time to Washington, D.C., in 2018 and live a short drive from Nationals Park, where Stephen regularly works out even during the offseason, according to The Washington Post.