Following incumbent Republican Rob Portman's announcement that he would not seek re-election, Vance declared his candidacy for the United States Senate.

Trump and Vance went on to win the election, defeating the Democratic ticket, incumbent vice president Kamala Harris and Minnesota governor Tim Walz.

[8] In March 2021, Peter Thiel gave $10 million to Protect Ohio Values, a super PAC created in February to support a potential Vance candidacy.

[27][28] On February 26, 2023, Vance wrote an op-ed in The Washington Post, supporting the provision of PPP style funds to those affected by the derailment, which some Republican senators criticized.

[29][30] On March 1, 2023, Vance and Senators Sherrod Brown, John Fetterman, Bob Casey, Josh Hawley, and Marco Rubio proposed bipartisan legislation to prevent derailments like the one in East Palestine.

In June 2023, Vance voted against raising the debt ceiling, standing against final passage of the Fiscal Responsibility Act of 2023[34] and saying it would result in "a reduced military in the face of a rising threat from China".

[35] In June 2023, Vance worked with Senator Elizabeth Warren of Massachusetts to claw back executive pay when big banks fail.

[36] In July 2023, Vance and Representative Marjorie Taylor Greene introduced legislation that would have made gender-affirming care for minors a federal crime, with penalties of up to 12 years in prison.

[49] Later that same day, Vance formally accepted his party's nomination for vice president of the United States at the 2024 Republican National Convention in Milwaukee, Wisconsin.

On December 14, 2024, Vance attended the 2024 Army–Navy Game, alongside Trump, Elon Musk, Daniel Penny, Pete Hegseth, Ron DeSantis, Mike Johnson, John Thune, Dave McCormick, Tulsi Gabbard, Joe Manchin, and Vivek Ramaswamy.

[58] In January 2023 Vance advocated for the U.S. Department of Justice to enforce the Comstock Act of 1873 to ban the mailing of drugs that induce abortion.

[59] In June 2024, the Supreme Court at least temporarily preserved access to mifepristone,[60] after which Trump said during a debate that he "agree[d] with their decision" and would not "block" the drug.

[76][77] Vance has expressed concern that large tech companies have too much influence in politics and the flow of information and has called to "break up" Google, as well as implying he believes Meta should be split up.

[78][79] He has said that Federal Trade Commission (FTC) chair Lina Khan is "doing a pretty good job", citing her antitrust enforcement against tech firms.

[81][82] In September 2024, Vance visited a Reading, Pennsylvania supermarket, where he complained that "a dozen eggs will cost you around $4" and blamed Kamala Harris for it.

[83][84] Vance has regularly framed himself as a union ally, even going so far as to explicitly support labor in the 2023 United Auto Workers strike, which many in his party criticized.

[72] AFL-CIO president and Democratic Party lobbyist Liz Shuler[92][93] has said: "A Trump–Vance administration would be a dream for corporate CEOs but a nightmare for workers.

[96][97] He has said concerns about the long-term solvency of the Social Security Trust Fund are overstated, and that increasing labor force participation and birth rate would sustain the system.

[98][99] In September 2024, Vance said "Haitian illegal immigrants" were "draining social services and generally causing chaos all over Springfield, Ohio.

[103] His father accused "morally bankrupt politicians ... JD Vance and Donald Trump" of using Aiden's "death for political gain", saying "This needs to stop now", and wishing that "the incessant group of hate-spewing people would leave us alone".

Dayton police responded, "there is no evidence to even remotely suggest that any group, including our immigrant community, is engaged in eating pets".

He claimed that mask mandates "failed to control the spread of respiratory viruses", "violated basic bodily freedom",[111] and were "unscientific".

"[117] In December 2024, responding to a post by Foundation for Defense of Democracies fellow Ivana Stradner criticizing Elon Musk's support for the far-right Alternative for Germany (AfD) party, Vance sarcastically replied by saying "It’s so dangerous for people to control their borders.

[122] He has said that Israel should win and end the war in Gaza "as quickly as possible" to enable the "Israelis and the Sunni Arab states" to form a united front against Iran.

[123] Vance has criticized the Biden administration for "depriving the Israelis of the precision-guided weapons" the country needs, and said that Hamas bears full responsibility for all civilian deaths.

[126] Vance repeated his criticism of the Biden administration in July 2024, saying: "Number one, you want Israel to get this war over and as quickly as possible because the longer it goes on, the harder their situation becomes.

"[132] In a 2024 speech, Vance said that "in 2003, I made the mistake of supporting the Iraq War", which he had served in as a combat correspondent in the Marine Corps, but that he later realized "that I had been lied to that the promises of the foreign policy establishment were a complete joke.

"[144][145] Vance and Trump's special envoy Keith Kellogg said that continued arms shipments to Ukraine and a heavily fortified demilitarised zone would ensure that Russia would not launch another invasion.

[146] In July 2024, after the British Labour Party won a landslide victory in the 2024 United Kingdom general election, Vance said in a speech at the National Conservatism Convention: "I was talking with a friend recently ... what is the first truly Islamist country that will get a nuclear weapon?

[147] Senior British officials, such as Angela Rayner, James Murray, and Andrew Bowie dismissed this statement, which echoed right-wing characterizations of Britain and Europe.