She lost the general election, receiving 23% of the vote and placing third behind Democrat Joseph E. Brennan and the winner, Independent candidate Angus King, her future Senate colleague.

[18] She served in this post until 1996, when she announced her candidacy for the U.S. Senate seat being vacated by her former boss, William Cohen, who retired to become United States Secretary of Defense under President Bill Clinton.

"[34] In a May 1997 interview, Collins stated her support for a proposal by Tom Daschle banning all abortions after the fetus is capable of living outside the womb except to save the life of the woman or protect her from physical injury.

Of an alternative measure proposed by Rick Santorum that would ban partial-birth abortion, Collins said it "ignores cases in the medical literature involving women with very serious physical health problems".

[37] In 2004, Collins was one of the primary sponsors of legislation overhauling the U.S. intelligence community by creating a new post, Director of National Intelligence, to oversee budgets and most assets of the spy agencies, and mandating that federal agencies establish minimum standards for states pertaining to issuing driver's licenses and birth certificates along with directing the United States Department of Homeland Security to form standards for ID used to board airplanes.

She said she had done so on procedural grounds, because the funding did not belong in a stimulus bill: "while worthwhile, [it does] not boost our economy," and "it does not make sense to include $870 million for pandemic flu preparedness.

The Pentagon announced that the Obama administration would not authorize Senate investigators to question intelligence agents who reviewed e-mails between Hasan and an extremist Islamic cleric before the shooting.

"[44] In May 2010, Collins and Snowe were the only two Republicans to vote for an unsuccessful Democratic measure that would have prevented bailouts, highlighted financial products of complexity and toughened consumer protection.

[48] In May 2013, following a report that the Internal Revenue Service had put additional scrutiny on conservative groups, Collins said the revelation "contributes to the profound distrust that the American people have in government" and added that she was disappointed that Obama "hasn't personally condemned this and spoken out".

[53] In May 2016, the Senate passed an appropriations bill containing an amendment by Collins that she said would help prevent the Department of Housing and Urban Development from gaining "national zoning authority for every neighborhood in our country".

She said that as a lifelong Republican she did not make the decision lightly but felt he was unsuitable for office, "based on his disregard for the precept of treating others with respect, an idea that should transcend politics".

She said she disagreed with "the easing of the sanctions because I think it sends the wrong message to Russia and to the oligarch and close ally of Mr. Putin, Oleg Deripaska, who will in my judgment continue to maintain considerable [ownership] under the Treasury's plan.

The bill required the Secretary of Transportation to request nominations and make determinations in regard to roads that would be designed under a voluntary, community-based program and was signed into law by Trump in September of that year.

[93] Toward the end of January 2021, Collins led a group of 10 Republican senators who requested that President Joe Biden join bipartisan negotiations when creating his COVID-19 economic relief package.

[104] Collins voted to confirm Ketanji Brown Jackson to the Supreme Court, making her one of the only three GOP senators to support her nomination, the other two being Lisa Murkowski and Mitt Romney.

[132][133] In 2020, Collins faced renewed criticism of her vote by progressive groups when Kavanaugh said states should be permitted to severely reduce access to and availability of abortion in his dissent in June Medical Services LLC v Russo.

[143][144][145][146] On May 11, 2022, Collins voted against the Women's Health Protection Act of 2022, a bill that would prohibit a variety of restrictions on access to abortion, on the basis that it went too far beyond the standards established in Roe v. Wade and Planned Parenthood v.

[147][148] Collins joined Murkowski and Senator Kyrsten Sinema in drafting the Reproductive Choice Act, alternative legislation that would codify Roe and Casey into federal law more narrowly.

[156] The bill also repeals Affordable Care Act's individual mandate, leaving thirteen million Americans uninsured and raising premiums by an estimated additional 10% per year.

[168] In 2008, Collins joined the bipartisan Gang of 20, which sought to break a deadlock on a bill allowing offshore drilling that would devote billions in proceeds to renewable energy development.

[169][170] In February 2017, Collins was the only Republican to vote against undoing an Obama administration rule that required coal mining companies to avoid contaminating local waterways.

[172][173] In 2017, Collins voted for the Tax Cuts and Jobs Act, allowing oil drilling in the Arctic National Wildlife Refuge, after unsuccessfully attempting to remove that part of the bill.

[177] In April 2008, Collins and Senators Ben Nelson and Evan Bayh met with Bush's advisor on Iraq and Afghanistan, Douglas Lute, and expressed support for a prohibition on spending for major reconstruction projects, the proposal requiring Iraqis to pay for its security forces to be trained and equipped and reimburse the American military for the estimated $153 million a month the military spent on fueling in combat operations in Iraq.

[180] In 2010, she called for the removal of Arnold Fields as Special Inspector General for Afghanistan Reconstruction, citing his repeated expressing of concern for the SIGAR and his disappointment with the Obama administration's "ongoing failure to take decisive action".

[181] In August 2017, Collins commended Trump for providing clarity after years of the U.S. lacking a "clear focus and defined strategy" with respect to Afghanistan and said he made the case that the Afghan government must participate "in defending its people, ending havens for terrorists, and curtailing corruption".

[182] Before Obama met President of the People's Republic of China Xi Jinping at an informal retreat in June 2013, Collins cosponsored legislation that would authorize the Commerce Department to investigate whether currency manipulation is a form of subsidization.

[199] In 2018, Collins co-sponsored the NICS Denial Notification Act,[200] legislation developed in the aftermath of the Stoneman Douglas High School shooting that would require federal authorities to inform states within a day after a person failing the National Instant Criminal Background Check System attempted to buy a firearm.

[226] In 2017 and 2019, Collins co-sponsored bills with Democratic senators to prevent Trump from banning transgender people from the United States military[227] and prohibit anti-LGBT housing discrimination.

[232] In 2021, Collins was one of 49 senators to vote for an amendment to the American Rescue Plan Act of 2021, which aimed to defund schools allowing transgender students to compete in sports.

After former Federal Communications Commission chairman Ajit Pai repealed net neutrality regulations in 2017, Collins and Senator Angus King announced they would support a bipartisan enactment of the Congressional Review Act to reverse the FCC's decision.