Collins is a Phi Beta Kappa graduate of St. Lawrence University. She worked for Senator William Cohen from 1975 until 1987, when she became chair of the Maine commission on financial regulation. She served in this position until 1992, when she briefly served as New England regional director of the National Small Business Administration. She then moved to Massachusetts and served as its Deputy Treasurer in 1993, but then moved back to Maine. She was the Republican candidate in the Maine gubernatorial election of 1994, but both she and the Democratic candidate, former Governor Joe Brennan, were defeated by the Independent candidate, Angus King. When Senator Cohen announced his retirement, Collins announced her Senate candidacy, and after a difficult three-way primary she defeated Democrat Joe Brennan in the general election. She was reelected in 2002 over State Senator Chellie Pingree (D) 58 42åP> In the U.S. Senate, Collins played an important role during the Senate's impeachment trial of Bill Clinton, when she and fellow Maine Senator Olympia Snowe sponsored a motion that would have allowed the Senate to vote separately on the charges and the remedy. When the motion failed, both Snowe and Collins subsequently voted to acquit, believing that while Clinton had broken the law by committing perjury, the charges did not amount to grounds for removal from office.

On May 23, 2005, Collins was one of fourteen moderate senators to forge a compromise on the Democrats' use of the judicial filibuster, thus blocking the Republican leadership's attempt to implement the so-called "nuclear option". Under the agreement, the Democrats would retain the power to filibuster a Bush judicial nominee only in an "extraordinary circumstance", and the three most conservative Bush appellate court nominees (Janice Rogers Brown, Priscilla Owen and William Pryor) would receive a vote by the full Senate.

Often labeled as a moderate or liberal Republican, Collins often breaks with her party. She voted against the ban on partial-birth abortions, the restrictions on travel to Cuba, harsher punishments for drug users, and she opposed amending the U.S. Constitution to prohibit same-sex marriages. On taxation and trade she has taken a more moderate line, voting against some trade agreements, most recently CAFTA. In 2001 she was one of only four Republicans to vote to limit the reduction in the top tax rate and to increase the amount of tax relief for those at the bottom of the income scale. In 2003 she was the only Republican to vote in favor of spending a portion of the tax cut reserved for upper-income payers on the building of hospitals in rural areas. She has voted against drilling in ANWR and in favor of increasing the average mile-per-gallon requirement for vehicles. In September of 2005, Collins cosponsored a resolution with Sen. Patrick Leahy (D-VT), which disapproved a new rule put in place by the Administrator of the Environmental Protection Agency that delisted coal and some other energy sources from the Clean Air Act. The resolution failed by a vote of 47-51.

Senator Collins is a member of The Republican Main Street Partnership and supports stem cell research. She is also a member of The Republican Majority For Choice, Republicans For Choice, The Wish List, Republicans For Environmental Protection and Its My Party Too.

In February 2006, TheWhiteHouseProject.org named Susan Collins one of its "8 in '08", a group of eight female politicians who could possibly run and/or be elected president in 2008.

Senator Collins was considered a possible choice to serve as the Secretary of Homeland Security if John Kerry had won the 2004 Presidential Election. Since 2002, she has been the Chairman of the Homeland Security and Governmental Affairs Committee, where she has developed a close working relationship with the committee's top Democrat, Connecticut Senator Joe Lieberman. If Kerry had won, such an appointment would also have provided Kerry with a Republican in his cabinet. Because of her expertise on homeland security and the high regard people in both parties hold for her, Senator Collins remains a possible choice for Secretary of Homeland Security following the 2008 Presidential Election, regarless of whether a Democrat or Republican is elected as the President of the United States.