Santarsiero was elected to the Lower Makefield Board of Supervisors in 2003. He organized the Southeastern Bucks League of Municipalities, a discussion forum for 19 townships and boroughs in lower Bucks County. In 2008, Santarsiero was elected to Pennsylvania's House of Representatives with 53% of the vote, defeating Republican challenger Pete Stainthorpe. Santarsiero defeated Republican challenger Rob Ciervo by 162 votes in 2010, securing his second term in office. In 2012, Santarsiero was elected with 58% of the vote, defeating Republican Anne Chapman. Santarsiero served on the Children & Youth, Education, Environmental Resources & Energy, and Transportation Committees. On May 4, 2017, Pennsylvania Attorney GeneralJosh Shapiro appointed Santarsiero as the first Chief Deputy Attorney General for Environmental Protection. He resigned his position in January 2018 in order to launch a bid for Pennsylvania Senate, District 10, the seat held by retiring Senator Chuck McIlhinney.
Santarsiero announced his candidacy for State Senate in Pennsylvania's 10th Senatorial District on January 27, 2018. The incumbent, Republican Chuck McIlhinney, did not seek reelection. Santarsiero defeated State RepresentativeMarguerite Quinn in the November 6th, 2018 general election to win the seat.
In early 2013, Santarsiero introduced a bill which would end the permitting of intrastate long gun purchases in Pennsylvania. The bill, which has never been brought to a vote, was the subject of controversy in Pennsylvania, drawing support from Cease Fire PA, Bucks Safe, the Peace Center, Keystone Progress, and Mayors Against Illegal Guns and opposition from the Second Amendment Action Group and the National Rifle Association. In 2016, PolitiFact.com found Santarsiero's claim that he "wrote Pennsylvania's Gun Safety Law" to be false.
Environment
Santarsiero has called for increased regulation of Marcellus Shale, natural gas, and hydraulic fracturing. In 2012, he introduced H.B. 2414, which would increase regulation of natural gas drilling. HB 2414 was a part of a six-piece legislative package known as the Marcellus Compact, sponsored by Pennsylvania Democrats to regulate the natural gas industry in the state. The legislation did not come to a vote.
Following the Citizens United Supreme Court Ruling, Santarsiero introduced a bill calling for a convention to amend the United States Constitution to allow states and the United States Congress to pass laws limiting the amount of money that any person or group can donate to federal or state elections. He has since reintroduced this resolution twice.