He attended Shawnee High School, in Medford, New Jersey where he was a stand-out pitcher and broke the state record for most strikeouts in a game. Sean was also a great hitter and led Shawnee to a state championship. Doolittle played for the University of Virginia as both a starting pitcher and first baseman. He formerly held the record for wins in a career for a Virginia pitcher — 22 — which has since been passed by Danny Hultzen. In 2005 and 2006, Doolittle was named to the USA National (Collegiate) Baseball Team.
Despite being injured for most of the 2009 season, Doolittle was ranked tenth in Oakland's farm system according to Baseball America. Doolittle missed the entire 2010 season while rehabbing from 2 knee surgeries. In the 2011 offseason, he was placed on Oakland's 40-man roster to be protected from the Rule 5 draft. After missing more than two years, Doolittle converted back to pitching, making his professional pitching debut in the instructional league in Arizona in 2011.
After just 26 professional innings, 25 of those at three minor league stops in 2012, Doolittle was called up to the majors on June 5, 2012 against the Texas Rangers pitching 1 and a third inning while striking out three with all fastballs and none going below 94 mph. He quickly became a key bullpen piece as the top lefty specialist earning his first career save on July 21 against the New York Yankees. He served as a set-up man for A's closer Grant Balfour the rest of the way as Oakland went on to win the AL West on the final day of the season.
Doolittle signed a five-year, $10.5 million extension with the Athletics on April 18, 2014.
Going into spring training, Doolittle developed a slider after being a fastball only pitcher. Doolittle and righty Luke Gregerson entered the regular season as late-inning setup pitchers for new closer Jim Johnson. However after an abysmal April, Johnson was removed from the exclusive closing role. Doolittle, Gregerson and Johnson spent the next 3 weeks pitching under closer by committee. Doolittle was ultimately named A's closer on May 20. Doolittle was one of six A's players named to the 2014 American League All-Star Team; he faced three batters late in the game - striking out two.
Doolittle began the 2015 season on the disabled list due to a shoulder injury.