Supreme attempted another presidential run in 2016. He embarked on a tour of 20 cities to build support for his campaign and sought to qualify for matching funds from the Federal Election Commission (FEC). He filed as a candidate in the New Hampshire Democratic presidential primary on November 21, 2015. He was not invited to return to the Lesser-Known Democratic Candidates Presidential Forum, due in part to him glitterbombing Randall Terry at the event in 2011. Shortly before the primary, he was observed questioning Republican candidates Chris Christie and Ted Cruz through a bullhorn. Supreme engaged Christie in an informal debate over his free pony platform, during which he accused Christie of hating ponies, and asked Ted Cruz whether he thought that water being used during waterboarding should include fluoride. Supreme received 256 votes in the primary on February 9, 2016, coming in fourth after former Maryland Governor Martin O'Malley, who had dropped out after the Iowa caucuses. On March 4, Supreme switched his affiliation to the Libertarian Party.He received the vote of a single delegate in the first round of presidential nomination voting at the 2016 Libertarian National Convention.
Supreme ran again for president in 2020 as a Libertarian. This also marks the first time that Supreme has run a "legitimate" campaign, focusing on real rather than satirical issues and using the slogan "In On The Joke". Supreme continued to use satirical humor, but he focused more on real issues. He called for ending foreign wars and voiced support for pardoning non-violent drug offenders, ending the war on drugs, and reducing incarceration, which he called his top priority. On the COVID-19 pandemic, Supreme criticized incumbent President Donald Trump, arguing that he should have paid better attention to the virus and made testing more widely available. He also promised to make COVID-19 illegal and, in a play on his camaign promise to go back in time and "kill baby Hitler," vowed to go back in time and "kill baby COVID." He pledged to create "COVID-19 free zones" because "they work so well for things like guns and drugs.