Mathias was elected to the Senate in 1968, unseating the incumbent Democrat, Daniel Brewster, who twenty years earlier had been his roommate while attending the University of Maryland School of Law.

For a few months in late 1975 and early 1976, Mathias considered running an insurgent presidential campaign in an attempt to stave off the increasing influence of conservative Republicans led by Ronald Reagan.

[7] Mathias' opponent in the general election was John R. Foley, a former judge who had unseated DeWitt Hyde in a Democratic landslide in the state two years prior.

[9] Mathias prevailed over Foley on election day in November 1960, unseating the one-term incumbent and becoming the first representative from Frederick County since Milton Urner in 1883.

[15] Concerning environmental issues, Mathias sponsored legislation to make the Chesapeake and Ohio Canal a national park, and supported other conservation initiatives along the Potomac River.

[18] Leading up to the United States Senate elections of 1968, Mathias' name was frequently mentioned as a potential challenger to Democratic incumbent Daniel Brewster, his college roommate.

[19] Mathias officially declared his candidacy for the Senate on February 10, 1968, calling for troop reductions in the Vietnam War, and identifying urban blight, racial discrimination, welfare reform, and improving public schools as major issues.

Brewster adopted a hard line stance on law and order, while Mathias advocated addressing the precipitating causes of poverty and the low standard of living in urban ghettos.

In June 1969, Mathias joined with fellow liberal Republican Hugh Scott of Pennsylvania in threatening a "rebellion" unless the Nixon administration worked harder to protect African American civil rights.

[24] Mathias' disagreements with the administration became well-known, causing columnists Rowland Evans and Robert Novak to name him the "new supervillain... in President Nixon's doghouse".

[25] Evans and Novak also commented that "not since [Charles Goodell] was defeated with White House connivance has any Republican so outraged Mr. Nixon and his senior staff as Mathias.

[25] Due to their differing ideologies, there was speculation that Mathias was going to be "purged" from the party by Nixon in a similar manner as Goodell in 1971, but these threats disappeared after the Watergate scandal escalated.

[20] In early 1974, the group Americans for Democratic Action rated Mathias the most liberal member of the GOP in the Senate based on twenty key votes in the 1973 legislative session.

Issues considered when rating senators included their positions on civil rights, mass transit, D.C. home rule, tax reform, and reducing overseas troop levels.

[20][28] As an advocate for campaign finance reform, Mathias refused to accept any contribution over $100 to "avoid the curse of big money that has led to so much trouble in the last year".

On two issues, however, Mathias argued to reform Congress and the U.S. tax system to address inflation and corporate price fixing, contrary to Mikulski.

In 1975, Mathias co-introduced legislation with Illinois Senator Adlai Stevenson III that would prohibit foreign aid to South Vietnam after June 30, 1975.

[34] After four months of consideration, Mathias decided in March 1976 to not seek the presidency, and asked for his name to be withdrawn from the Massachusetts primary ballot, where it had been added automatically.

[35] However, despite his pledge to support the Republican candidate, Mathias' criticism of the party did not wane, stating that "over and over again during the primaries, I have felt uncomfortably like a member of the chorus in a Greek tragedy".

[36] In a further criticism of his party's neglect of liberal voters, Mathias commented: I've had to deal with some hard truths... People don't like to hear we've got only 18 percent of the electorate.

However, party leaders were uneasy with the idea of allowing Mathias to team up with liberal Democrat and subcommittee chairman Birch Bayh, and voted instead for William L. Scott as ranking member.

[42] In 1982, Mathias chaired a bipartisan Senate inquiry into the methods used by the FBI in the Abscam corruption investigation, which found that dozens of officials had been named for accepting bribes without basis.

He had a private lunch with Le Grelle and his friend Daniel Jouve, during which they suggested the possibility to have a Space Shuttle at the 1983 Paris Air Show.

[67] On February 17, 1983, James M. Beggs wrote back: "Dear Senator Mathias: Having a Space Shuttle Orbiter at the 1983 Paris Air Show as you suggested in your letter of December 27, would, indeed, be a tremendous advertisement for American technology.

He held liberal views on abortion, defense spending, and the Equal Rights Amendment,[11] and, along with Senator John Warner of Virginia, was one of the sponsors of a bill to authorize the construction of the Vietnam Veterans Memorial.

[73] In discussing Mathias' retirement, Tom Wicker of The New York Times commented that "he was fair, flexible, concerned, able to rise above partisanship but not above responsibility".

When Wicker asked him which senators he respected the most, Mathias listed J. William Fulbright (D), Jacob Javits (R), John Sherman Cooper (R), Cliff Case (R), Phil Hart (D), Mike Mansfield (D), and George Aiken (R), because "each one of those people would take an issue on his own responsibility...

He played an important role in the Final Report, Book Five, "The Investigation of the Assassination of President John F. Kennedy : Performance of the Intelligence Agencies, 94th Congress, 2nd Session, 1976".

After touring the bay shoreline in 1973, he sponsored legislation that led to a study by the United States Environmental Protection Agency (EPA) two years later, which was one of the first reports that made the public aware of harmful levels of nutrients and toxins in the waters.

[78] In 2003, thirty years after he launched a study of the Chesapeake, Mathias was recognized by the Army Corps of Engineers for the influential role he played initiating restoration efforts.