On 28 March 2017, Drahoš announced his intention to stand in the 2018 presidential election. On 24 April 2017, he started gathering the signatures required to be registered as a candidate. In July 2017, after meeting with Drahoš, the leaders of Populars and Mayors, Pavel Bělobrádek and Petr Gazdík, announced that they would ask their respective parties members to nominate and endorse Drahošs candidacy. Mayors and Independents endorsed Drahoš on 25 July 2017 while the Christian and Democratic Union – Czechoslovak People's Party (KDU–ČSL) endorsed him on 14 November 2017. Young Social Democrats also endorsed Drahoš on 9 December 2017. Polls in late 2017 showed Drahoš as the second strongest candidate behind Zeman.
Drahoš received campaign donations from several influential businessmen, including Dalibor Dědek, Jiří Grygar and Luděk Sekyra. Drahoš started gathering signatures for his nomination in May 2017. On 19 August 2017, Drahoš announced he had gathered 78,000 signatures. He submitted his nomination on 3 November 2017 with 142,000 signatures.
On 4 November 2017 on Facebook, Drahoš criticized Mirek Topolánek, who had announced his candidacy that day, describing Topolánek as similar to Miloš Zeman and calling his candidacy a bad joke. The two candidates met during a presidential debate at Charles University; Drahoš reflected that the status he posted was "Topolánek-like", to which Topolánek replied that it was written either by "a woman or PR mage".
Drahoš received media attention when he expressed his fear that the election could be influenced by Russia. He met outgoing Prime Minister Bohuslav Sobotka to discuss the matter and stated he would also meet the new Prime Minister Andrej Babiš. The incumbent president Miloš Zeman criticized Drahoš and compared his actions to Hillary Clinton's when she lost to Donald Trump.
Drahoš received criticism when he published a status on social media about Václav Klaus' amnesty, when it was revealed that he had copied a similar status by his fellow presidential candidate Michal Horáček. Drahoš apologised and attributed the mistake to an external member of staff.
The first round was held on 12 and 13 January 2018. Drahoš received 1,369,601 (26.6%) votes, and advanced to the second round against the incumbent president Miloš Zeman. In the second round, held on 26–27 January 2018, Drahoš received 48.63% of the vote and thus lost to Zeman. Drahoš conceded defeat to Zeman, telling a crowd of his supporters that "I would like to congratulate election winner Miloš Zeman".