Strickland was called up to the majors for the first time on September 1, 2014. He pitched one scoreless inning of relief against the Colorado Rockies later that day. In the 2014 regular season, Strickland appeared in 9 games, allowing 5 hits and no runs in 7.0 innings pitched.
In Game 1 of the 2014 National League Division Series versus the Washington Nationals, Strickland entered the game with the bases loaded and two outs in the sixth inning and struck out Ian Desmond to preserve the Giants' lead. In Game 2, Strickland recorded the save in the longest (by time, tied for longest in innings) playoff game in Major League history, as the Giants defeated the Nationals 2–1 in 18 innings. However, Strickland set a postseason record for a reliever by allowing six home runs, even though the Giants went on to defeat the Kansas City Royals in the 2014 World Series.
In a May 29, 2017, game against the Washington Nationals, Strickland hit Bryce Harper's right hip with a 98-mph fastball, which resulted in a benches-clearing brawl. Strickland had to be physically removed from the field by teammates after exchanging several punches with Harper. He received widespread criticism for his role in starting the brawl, as sports analysts and Harper have suggested that the intentional hit-by-pitch was the result of a grudge from the two home runs by Harper against him in the 2014 National League Division Series, a series the Giants ended up winning in 4 games en route to a World Series championship. The next day, on May 30, he was suspended for six games.