Lugar continued to be reelected until 2012, when he was defeated by Indiana State Treasurer Richard Mourdock in the Republican primary by 21 points, who subsequently lost in the general election to Democrat Joe Donnelly, ending his 36-year tenure in the U.S. Senate.

Much of Lugar's work in the Senate was toward the dismantling of nuclear, biological, and chemical weapons around the world, co-sponsoring his most notable piece of legislation with Georgia Democrat Sam Nunn: the Nunn–Lugar Act.

[21][22] He was the first six-term U.S. senator to lose his seat in a primary election since Kenneth McKellar in 1952.Future governor of Indiana Mitch Daniels served as Lugar's chief of staff from 1977 to 1982.

[24] In his first months, Lugar backed legislation prompting the Senate to adopt a stringent code of ethics intended to assist with the restoration of public confidence in Congress.

[30] On October 15, 1981, Lugar voted against the recommendation of the disapproval toward the Reagan administration's intent to sell Awacs radar surveillance planes and other air-combat equipment to Saudi Arabia.

[35] On December 23, 1982, Lugar voted in favor[36] of a 5 cent a gallon increase on gasoline taxes across the U.S. imposed to aid the financing of highway repairs and mass transit.

"[67] In a September 28, 1988, news conference, Democratic vice-presidential nominee Lloyd Bentsen cited Lugar as one of three "heavyweight" Republican senators who were more qualified for the vice presidential nomination than Quayle.

[69] In February 1990, Lugar announced that the congressional group President Bush named to observe Nicaragua elections the following month was disbanded following their being denied visas by the Nicaraguan government.

[73][74] on August 21, 1990, Lugar told reporters that the move to a marketing economy on the part of Vietnam had created the possibility for American investment provided that differences between Washington and Hanoi be resolved.

"[78] In June 1991, Lugar joined fellow Senators William Cohen and John Warner in revealing their dissent with space-based weapons, a central component of the Bush administration's version of the Strategic Defense Initiative, in a letter and speeches.

[79] On November 25, 1991, the Senate voted in favor of approving the Bush administration-backed package to transfer $500 million of the Pentagon budget to assist with dismantling Soviet nuclear weapons.

[80] In support of the measure, Lugar said, "We can either seize the opportunity for cooperative efforts in this field now or witness a quantum leap in the proliferation of weapons of mass destruction in the next few years.

[85] Lugar was of the view that the United States wanted a full partnership with Europeans that could only arise from "recognition on their side that our men and women in the armed forces are taking risks right now".

[92] On February 12, 1999, Lugar voted in favor of both articles of impeachment against President Clinton,[93] calling his relationship with White House intern Monica Lewinsky "shameless, reckless and indefensible",[94] and criticizing him for creating a negative environment.

"Simply to be near him in the White House has meant not only tragic heartache for his wife and his daughter but enormous legal bills for staff members and friends who admired him and yearned for his success but who have been caught up in his incessant 'war room' strategies to maintain him in office.

During the August recess of 2005, Lugar and then-freshman Senator Barack Obama of neighboring Illinois visited Russia, Azerbaijan, and Ukraine to inspect nuclear facilities there.

In January 2007, President Bush signed into law the Lugar–Obama Proliferation and Threat Reduction Initiative, which furthered Lugar's work with Senator Sam Nunn in deactivating weapons in the former Soviet Union.

[99][104] On January 13, 2009, Lugar participated in the confirmation hearing for Secretary of State nominee Hillary Clinton, raising questions on the potential conflict of interest between her husband Bill's charitable activities and her new position.

He was on the ballot in seven of the nine contests on Super Tuesday on March 5, winning 1% in Colorado, Connecticut, and Maryland, 2% in Massachusetts, 3% in Maine and Rhode Island and 14% in Vermont, which was the best result he managed, though he still only came in 4th.

[110] He remained on the ballot in a number of states, winning 2% of the vote in Florida, then 1% each in Oregon, Illinois, Ohio, and California, 5% in Pennsylvania and 1% in North Carolina and West Virginia.

"[132] Two days later, on June 27, 2007, Lugar said that Congressional measures aimed at curtailing U.S. military involvement in Iraq – including "so-called timetables, benchmarks" – have "no particular legal consequence", are "very partisan", and "will not work".

[145] In a television interview on September 11, 1983, amid President Reagan not defining the penalties for American casualties in the Middle East, Lugar stated the US position in Lebanon was "clearly defensive", but concurred that issue was debatable.

[149] Lugar was influential in gaining Senate ratification of treaties to reduce the world's use, production and stockpiling of nuclear, chemical, and biological weapons, and spearheaded many bipartisan nonproliferation initiatives.

In 1991 he initiated a partnership with then-Senate Armed Services Committee Chairman Sam Nunn aiming to eliminate latent weapons of mass destruction in the former Soviet Union.

Nearly identical pro-transparency measures, aimed at curbing natural resource-related corruption in the developing world, were subsequently adopted by the European Union and Canada, making extractive industry payment disclosure a global standard.

[156] In a November 2017 interview, Lugar stated that President Donald Trump had not "demonstrated civility in his leadership" and that his usage of Twitter and "other bombastic avenues" were not solving issues.

In June 2012, he was conferred with the Grand Collar of the Order of Lakandula by President Benigno S. Aquino III for his contributions to the enhancement of the Philippine-US alliance and friendship[163] as well as Poland's Knight of Freedom Award for his actions and support of the Polish accession process to NATO structures.

Ambassador to Georgia at the time, Richard Norland, signed an agreement with then-Georgian Prime Minister Irakli Garibashvili to transfer custody of the Center to the NCDC during the 2014 World Congress on Chemical, Biological, Radiological and Nuclear Science & Consequence Management.

"[196] Lugar's defeat in the 2012 Senate Republican primary was written of as a sign of the national GOP base's escalation into strict support for the traditional views aligned with the right.

[198] Geoffrey Kabaservice cast doubts on this view: "It may be that his bipartisanship and comparative moderation contributed to his loss, or his defeat may simply have reflected the political truism that young blood drives out the old.