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.
Sean made his professional debut on June 18, 2007 and at one point was considered a top prospect. His brother, Ryan Doolittle is also a part of the Athletics' farm system.
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 place 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 the rest of the way as the A's won the AL west
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, along with Luke Gregerson were supossed to be late inning pitchers to Jim Johnson. Johnson was pulled out of the closers role early in the season so Doolittle and Gregerson served a committee along with Johnson. Doolittle was named A's closer on May 20 after serving in the committee. Doolittle was one of the six A's players named 2014 all-stars, he faced three batters in the all-star game striking out two. He tied an A's record of most saves by a lefty pitcher on August 5.