In April 2020, Caputo was appointed as assistant secretary of public affairs in the Department of Health and Human Services in the Trump administration.

He worked for the Reagan Administration with Oliver North, and later as director of media services on the campaign for President George H. W. Bush in the 1992 United States presidential election.

[5] On September 14, 2020, Caputo posted a Facebook video in which he claimed that "there are hit squads being trained all over this country" to mount armed opposition to a second term for President Trump.

[9][10] Caputo's early public relations work was in Hawaii while with the United States Army, which he joined directly after finishing high school.

[9] After his work for the Reagan Administration he served as assistant director of the House of Representatives Gallery of the Radio and Television Correspondents' Association.

[11][13] His task was to increase Putin's public relations standing, specifically his support level in the U.S.[15][13][12] During his residence in Russia, he became a business partner and close friend of Sergey Petrushin on or about 1997.

"[27] Paladino explained his hiring choice of Caputo as campaign manager: "I'm facing some major demons here, and I needed someone who could go right back on top of them in a matter of minutes.

"[1] Donald Trump hired Caputo in 2014 to launch an astroturfing campaign in support of his stalking-horse bid for the Buffalo Bills.

When Trump placed his bid and was disallowed ties to the organization, Caputo retaliated by engaging in a smear campaign against other bidders: Jon Bon Jovi and Maple Leaf Sports & Entertainment.

"[32] Caputo told USA Today that he attributed the leaks to disaffected members of the Stop Trump movement, whom he called "anti-Trump zealots".

He said it was because the MMWR reporting contained "political content" as well as scientific information, adding that the changes suggested by his office were "infrequently" accepted by CDC.

[2] Citing concerns about the political leanings of CDC scientists, Caputo delayed for a month the publication of a report on hydroxychloroquine as a treatment for COVID-19 that concluded "the potential benefits of these drugs do not outweigh their risks.

[45] Caputo was the key figure in a planned HHS advertising campaign, funded with $300 million requisitioned from the CDC, which aimed to "defeat despair" about COVID-19 by airing video interviews between administration officials and celebrities.

Also, the company hired to film the interviews, which is headed by a business associate of Caputo's, had no experience with public health campaigns and struggled with the amount of work required to produce the videos.

[47] Senior House Democrats launched an investigation into a $250 million contract awarded to a market research firm, and questioned the political motivations behind airing such a campaign right before the 2020 presidential election.

Caputo added that left-wing "hit squads being trained all over this country" were preparing an armed insurrection after the 2020 presidential election, advising his listeners to "buy ammunition".

[5] On September 14, Caputo's hometown newspaper, The Buffalo News, released an editorial calling for his removal, "(...) What's lunacy is for paranoia and political calculations to be coloring the dissemination of scientific knowledge during a pandemic.

[53] Two days after Alexander was ousted and Caputo went on leave, the CDC reversed its much-criticized statement saying that asymptomatic people who have been in close contact with a person infected with the coronavirus did not need to receive COVID-19 testing;[54] the statement had been forced through at the direction of HHS leadership and the White House over the objections of scientists and without going through the usual CDC scientific review process.

[29][14][30] During a March 20, 2017, hearing, Representative Jackie Speier questioned FBI Director James Comey about Caputo, and cited employment with Gazprom and history in Ukraine.

[30] Caputo told the House Intelligence Committee: "The only time the President and I talked about Russia was in 2013, when he simply asked me in passing what it was like to live there in the context of a dinner conversation.

[58] While working in Russia in the 1990s, Caputo met and married a Russian student studying astrophysics; their marriage ended in a divorce.

[29][14][9] On September 24, 2020, a spokesman for Caputo's family announced that he had been diagnosed with metastatic head and neck cancer which originated in his throat.