Theresa May's tenure as Prime Minister of the United Kingdom began on 13 July 2016 when she accepted an invitation of Queen Elizabeth II to form a government, succeeding David Cameron, and ended on 24 July 2019 upon her resignation. May's premiership was dominated by Brexit, terrorist attacks in Westminster, the Manchester Arena and London Bridge, the Grenfell Tower fire, and the Salisbury poisonings. As prime minister, May also served simultaneously as First Lord of the Treasury, and as Minister for the Civil Service. She also served as Leader of the Conservative Party.

May was elected unopposed after her opponent, Andrea Leadsom, withdrew from the final round of the 2016 leadership election; May became Conservative leader on 11 July 2016, and she became prime minister two days later. She began the process of withdrawing the UK from the European Union, triggering Article 50 in March 2017. The following month, she announced a snap general election, with the aims of strengthening her hand in Brexit negotiations and highlighting her "strong and stable" leadership. This resulted in a hung parliament in which the number of Conservative seats had fallen from 330 to 317, despite the party winning its highest vote share since 1983. The loss of an overall majority prompted her to enter a confidence and supply arrangement with the Democratic Unionist Party (DUP) of Northern Ireland to support a minority government.

May carried out the Brexit negotiations with the European Union, adhering to the Chequers Plan, which resulted in her draft Brexit withdrawal agreement. She also announced a £20 billion increase in funding to the National Health Service through the NHS Long Term Plan, established the first-ever Race Disparity Audit and launched a 25 Year Environment Plan, amending the Climate Change Act 2008 to end the UK's contribution to global warming by 2050. Unemployment in the United Kingdom fell to record lows, the lowest jobless rate since 1975. Her government also passed legislation cracking down on knife crime and giving extra powers to law enforcement and intelligence services to combat terrorism, published the 2017 Industrial Strategy White Paper and signed an immigration treaty with France to stem illegal border crossings in January 2018.

Although May did not succeed in getting much of her Brexit legislation through Parliament, her government was nevertheless responsible for passing the Great Repeal Act and for negotiating and approving the near-entirety of the UK's terms of exit from the EU. Three budgets were passed during her tenure: the first in March 2017, the second in November 2017 and the third and final in October 2018. May was also a prominent figure in leading the international condemnation and response to Russia over the Salisbury poisonings of Sergei and Yulia Skripal in March 2018. May survived two votes of no confidence in December 2018 and January 2019, but after versions of her draft withdrawal agreement were rejected by Parliament three times and her party's poor performance in the May 2019 European Parliament election, she left office on 24 July and was succeeded by Boris Johnson, her former Foreign Secretary. May is viewed unfavourably in historical rankings and public opinion of British prime ministers.

In a referendum held on 23 June 2016, Britain voted to withdraw from the European Union, with a result of 52% for withdrawal and 48% for remaining within the union. David Cameron, who as prime minister had campaigned to remain within the European Union, announced on 24 June 2016, immediately following the announcement of the referendum results, that he would resign from his post. Following the first stages of the Conservative Party leadership election to succeed him, Home Secretary Theresa May's only remaining competitor, Andrea Leadsom, withdrew from the race on 11 July 2016. Following this announcement, Cameron said that he would step down from his post on 13 July. Cameron formally tendered his resignation to Queen Elizabeth II on that day, who subsequently appointed May as his successor. In her first speech as prime minister, May paid tribute to Cameron, saying "In David Cameron, I follow in the footsteps of a great, modern Prime Minister. Under David's leadership, the government stabilised the economy, reduced the budget deficit, and helped more people into work than ever before. But David's true legacy is not about the economy but about social justice. From the introduction of same-sex marriage, to taking people on low wages out of income tax altogether; David Cameron has led a one-nation government, and it is in that spirit that I also plan to lead."

When appointed by the Queen on 13 July 2016, May became the UK's second female prime minister, after Margaret Thatcher, and the nation's first female Prime Minister of the 21st century. She told the media on 11 July 2016 that she was "honoured and humbled" to ascend to the role.

Responding to some calls for a general election (reported by the news media) to confirm her mandate, "sources close to Mrs May" said there would be no such election, according to the BBC. In a speech after her appointment, May emphasised the term Unionist in the name of the Conservative Party, reminding all of "the precious, precious bond between England, Scotland, Wales and Northern Ireland." By 15 July 2016, May had travelled to Edinburgh, Scotland to meet with first minister Nicola Sturgeon, to reinforce the bond between Scotland and the rest of the country. "This visit to Scotland is my first as prime minister and I'm coming here to show my commitment to preserving this special union that has endured for centuries," she explained. After a meeting at Bute House, May offered the following comment about Scotland's role in the negotiations about the UK's exit from the EU: "I'm willing to listen to options and I've been very clear with the First Minister today that I want the Scottish government to be fully engaged in our discussion."

In August 2016, May launched an investigation aimed at identifying and reducing racism within public services.