In 2008, as a sophomore, Strasburg was converted to a full-time starting pitcher. He went 8–3 with a 1.58 ERA and 134 strikeouts in 98 ⁄3 innings. Four of his thirteen starts in 2008 were complete games, two of which were shutouts. On April 11 of that year, he struck out a Mountain West Conference record 23 batters in a game versus the University of Utah. He also gained eight miles per hour on his fastball, regularly working in the upper 90s and touching 100 mph.

Strasburg was named to the United States national baseball team on June 24, 2008. In that role he appeared in the 2008 World University Baseball Championship, held in late July. The United States won the gold medal in the competition.

Strasburg ended up with a 1–1 record, a 1.67 ERA, and a bronze medal for the Olympics, as the United States won its following contest against Japan 8–4. He won the USA Baseball Richard W. “Dick” Case Player of the Year Award in 2008.

Strasburg finished his junior year, the 2009 season, 13–1 with a 1.32 ERA, 59 hits allowed, 16 earned runs, 19 walks, and 195 strikeouts in 109 innings pitched. In his final home start on May 8, 2009, Strasburg threw his first career no-hitter while striking out 17 Air Force Falcons batters. His lone loss came against the Virginia Cavaliers in the NCAA Regionals as Virginia advanced toward the College World Series, but he still struck out 15 in seven innings during the loss. He won the Dick Howser Trophy and the National Pitcher of the Year Award.

On June 9, 2009, Strasburg was drafted number one overall in the 2009 Major League Baseball draft by the Washington Nationals. On August 17, 2009, he signed a record-breaking four-year, $15.1 million contract with the Nationals, just 77 seconds before the deadline, shattering a dollar-amount record previously held by Mark Prior, who signed for $10.5 million in 2001. Strasburg is represented by agent Scott Boras.

Strasburg made his professional debut on October 16, 2009, starting for the Phoenix Desert Dogs in the Arizona Fall League at Phoenix Municipal Stadium. He was selected to play in the league’s Rising Stars Showcase, but was unable to participate due to a minor neck injury. He also won Pitcher of the Week honors for the week of November 2, 2009 and led the AFL with four wins. Before the 2010 season started, Baseball America named Strasburg as the top pitching prospect, and the second-best overall prospect behind Jason Heyward.

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.

Strasburg made his first rehab start on August 7, 2011 for the Hagerstown Suns. Strasburg made six rehab starts during the 2011 minor league season throwing a total of 20 ⁄3 innings, with 29 strikeouts, compiling a 3.49 ERA and a 1–1 record. He then made five starts during the 2011 major league season, his first coming against the Los Angeles Dodgers on September 6. That year he threw for 24 innings, struck out 24, compiled a 1.50 ERA and a 1–1 record.

As part of Strasburg’s rehabilitation from his Tommy John surgery, and as a precaution due to his low innings total in 2011, the Nationals decided to limit the number of innings Strasburg would throw in the 2012 season. Although the number was never official, rumors started that Strasburg’s limit would be between 160 and 180 innings. It was also decided that Strasburg’s shutdown would be final; he would not pitch in the playoffs. Dr. Lewis Yocum, the surgeon who operated on Strasburg’s elbow, agreed in 2011 that Strasburg’s 2012 innings total should be limited, although he did not consult with Nationals General Manager Mike Rizzo or Strasburg during the season. Teammate Jordan Zimmermann underwent a similar process the year before.

In April 2012, Strasburg accumulated an NL-best 34 strikeouts and second-best 1.13 ERA. He totaled six walks and did not give up a home run. Consequently, he was named NL Pitcher of the Month. On May 20, Strasburg went 2-for-2 as a hitter in a game against the Baltimore Orioles and hit his first career home run, a solo shot off of Wei-Yin Chen. In his June 13 start against the Toronto Blue Jays, Strasburg became the first pitcher of the year to strike out 100 batters. On July 1, Strasburg was elected to his first All-Star Game, alongside teammates Gio González, Ian Desmond, and Bryce Harper.

Strasburg’s high profile and the success of the Nationals in the 2012 season made the innings limit a topic of national conversation. In addition to baseball writers, a number of other figures made their views on the topic known, including football broadcasters Troy Aikman and Terry Bradshaw, basketball reporter Stephen A. Smith, and even prominent politicians such as Rudy Giuliani and Mitch McConnell. Rizzo defended the decision to shut down Strasburg and criticized the buzz surrounding it: “It’s a good conversational piece, it’s a good debatable subject. But most of the people that have weighed in on this know probably 10 percent of the information that we know, and that we’ve made our opinion based upon.”

Strasburg pitched Opening Day for the Nationals at Nationals Park in Washington, D.C., on April 1, 2013. He went seven innings, giving up no runs and three hits and recording three strikeouts. Following the first batter of the game, Juan Pierre, he retired nineteen straight batters. Strasburg earned the decision, a win, with a final score of 2–0.

Strasburg achieved milestones in longevity in 2013. He pitched into the 8th inning for the first time in his big-league career on May 16, in a win against his hometown San Diego Padres, and in subsequent starts on May 26 and July 24. On August 11, 2013, Strasburg pitched his first career complete game, throwing a 6–0 shutout over the Philadelphia Phillies with 10 strikeouts and 4 hits.

He was ejected for the first time in his MLB career on August 17, 2013 by umpire Marvin Hudson for intentionally pitching at Braves batter Andrelton Simmons in the second inning of a Nationals-Braves game. Prior to the ejection, Hudson warned both teams after Strasburg hit Justin Upton with a first-pitch fastball following a Braves home run.

During the 2014 season, analysts noted a slight adjustment in Strasburg’s pitching mechanics, as he moved his back foot to rest against rather than partially atop the pitching rubber when going into his throwing motion. Strasburg explained that he had been reluctant to make the change but had come to believe it would improve his development. “I didn’t feel comfortable at first. Working at in between starts, it’s just become second nature,” he told The Washington Post. Strasburg said he had noticed an improvement in his balance and timing as a result of the new foot placement.

On June 24, 2014, Strasburg stated in an interview that he was going to stop chewing tobacco in the wake of his college coach Tony Gwynn’s death, although he admitted to The Washington Post two years later that he had not yet completely kicked the habit.

Strasburg signed a 7-year, $175 million extension to remain with the Nationals. With the extension, Strasburg became the first National to receive an opt-out clause in his contract, which allows him to elect free agency after the 2019 or 2020 seasons if he desires. On June 26, 2016, he was placed on the 15-day disabled list due to an upper back strain. He returned on July 3 against the Cincinnati Reds, where he took a no-hitter through 6.2 innings until being lifted from the game after throwing 109 pitches. The no-hitter was broken up in the 8th inning, but the Nationals still won 12-1. On July 8, Strasburg became the first pitcher since 1912 to start 12-0. His streak of consecutive wins ran to 16, including 13 decisions in the 2016 season, before it was snapped by the Los Angeles Dodgers on July 21. On August 22, Strasburg was again placed on the 15-day disabled list due to right elbow soreness.

In 2018 he was 10-7 with a 3.74 ERA in 22 starts, in which he struck out 156 batters in 130.0 innings.

In 2019, Strasburg was 18-6 with a 3.32 ERA. He finished the regular season leading the National League in wins (18), and he finished second in strikeouts (251) behind Jacob deGrom; both were career highs.

After winning the World Series, Strasburg opted out of the remaining four years on his contract and became a free agent for the first time in his career. On December 9, 2019, Strasburg agreed to a seven-year, $245 million contract to return to the Nationals. In the contract, Strasburg has a specific request that the Nationals Park stays open everyday in the off-season so that he could continue to work out. The $35 million annual average value of the contract was at the time the largest amount received by a pitcher in MLB history.

Strasburg began the 2020 shortened season on the injured list (IL); he made his 2020 debut on August 9, 2020. On August 14, Strasburg left the second game he started, after facing only three batters. The following day, Strasburg went back to the IL with a nerve issue in his pitching hand.