After school, Neil attended the University of Glasgow, where he edited the student newspaper, the Glasgow University Guardian, and dabbled in student television. He was a member of the Dialectic Society, the Conservative Club and participated in Glasgow University Union inter-varsity debates. In 1971, he was chairman of the Federation of Conservative Students. He graduated in 1971, gaining an MA with honours in political economy and political science; he had been tutored by Vince Cable and had a focus on American History.

After his graduation, Neil briefly worked as a Sports correspondent for local newspaper, the Paisley Daily Express, before working for the Conservative Party as a research assistant. In 1973, he joined The Economist as a correspondent and was later promoted as Editor of the publication's section on Britain.

Neil was Editor of The Sunday Times from 1983 to 1994. His hiring was controversial. It was argued that he was appointed by Rupert Murdoch over more experienced colleagues, such as Hugo Young and Brian MacArthur.

Opposition to perceived public school and Oxbridge attitudes was a hallmark of Neil's Sunday Times editorship. Neil regards the newspaper's revelation of details of Israel's nuclear weapons programme in 1986, by using photographs and testimony from former Israeli nuclear technician Mordechai Vanunu, as his greatest scoop as an Editor. During his editorship, the newspaper lost a libel case over claims that it had made concerning a witness, Carmen Proetta, who was interviewed after her appearance in the Death on the Rock documentary on the Gibraltar shootings. One of The Sunday Times journalists involved, Rosie Waterhouse, resigned not long afterwards.

While at The Sunday Times in 1988, Neil met the former Miss India, Pamella Bordes, in a nightclub, an inappropriate place for someone with Neil's job according to Peregrine Worsthorne. The News of the World suggested Bordes was a call girl. Worsthorne argued in an editorial article "Playboys as Editors" in March 1989 for The Sunday Telegraph that Neil was not fit to edit a serious Sunday newspaper. Worsthorne effectively accused Neil of knowing that Bordes was a prostitute. He certainly did not know about Bordes, which the Telegraph had accepted by the time the libel case came to High Court of Justice in January 1990, but the paper still defended their coverage as fair comment. Neil won both the case and £1,000 in damages plus costs.

In 1988 he became founding chairman of Sky TV, also part of Murdoch's News Corporation. Neil was instrumental in the company's launch, overseeing the transformation of a downmarket, single-channel satellite Service into a four-channel network in less than a year. Neil and Murdoch stood side by side at Sky's new headquarters in Isleworth on 5 February 1989 to witness the launch of the Service. Sky was not an instant success; the uncertainty caused by the competition provided by British Satellite Broadcasting (BSB) and the initial shortage of satellite dishes were early problems.

As well as Neil's newspaper activities he has maintained a television career. While he worked for The Economist, he provided news reports to American networks. At The Sunday Times, he contributed to BBC, both radio and television. He commented on the various controversies provoked by the paper while he was Editor. During the 1990s, Neil fronted political programmes for the BBC, notably Despatch Box on BBC Two, and Is This Your Life? (made by Open Media for Channel 4), which was nominated for a BAFTA award for "Best Talk Show" and on which Neil interviewed a wide variety of personalities, from Albert Reynolds and Morris Cerullo to Jimmy Savile and Max Clifford. He acted as a television newsreader in two films: Dirty Weekend (1993) and Parting Shots (1999), both directed by Michael Winner.

During Neil's time as Editor, The Sunday Times backed a campaign to prove that HIV was not a cause of AIDS. In 1992 Neil was criticised by anti-Nazi groups and historians like Hugh Trevor-Roper for employing the Holocaust denier David Irving to translate the diaries of Joseph Goebbels.

Neil's departure from his role as Sunday Times Editor was officially reported in 1994 as being merely temporary, as he was to present and edit a current affairs show for Fox in New York. "During my time, the Sunday Times has been at the center of every major controversy in Britain", he said at the time. "These are the kind of journalistic values I want to reproduce at Fox". Neil's new television programme did not make it to air. A pilot produced in September had a mixed internal response, and Murdoch cancelled the entire project in late October. Neil did not return to his job as Sunday Times Editor.

Neil became a contributor to the Daily Mail. In 1996, he became editor-in-chief of the Barclay brothers' Press Holdings group of newspapers, owner of The Scotsman, Sunday Business (later just The Business) and The European. Press Holdings sold The Scotsman in December 2005, ending Neil's relationship with the newspaper. Neil has not enjoyed great success with the circulations of the newspapers (indeed The European folded shortly after he took over). The Business closed down in February 2008. He exchanged his role as chief executive of Press Holdings for chairman in July 2008.

Neil was an early advocate of the 2003 invasion of Iraq, describing the case for war and regime change advanced by Tony Blair and George W. Bush as "convincing" and "masterful". Neil claimed, in 2002, that Iraq had "embarked on a worldwide shopping spree to buy the Technology and material needed to construct weapons of mass destruction - and the missile systems needed to deliver them across great distances", and that "the suburbs of Baghdad are now dotted with secret installations, often posing as hospitals or schools, developing missile fuel, bodies and guidance systems, chemical and biological warheads and, most sinister of all, a renewed attempt to develop nuclear weapons." He also claimed that Saddam Hussein would provide Al-Qaeda with weapons of mass destruction and had links to the September 11 attacks.

In June 2008, Neil led a consortium which bought talent agency Peters, Fraser & Dunlop (PFD) from CSS Stellar plc for £4 million. Neil will be chairman of the new company in addition to his other activities. Neil served as Lord Rector of the University of St Andrews from 1999 to 2002.

Neil played an important part of the BBC general election night coverage in both 2010 and 2015. Neil interviewed various celebrities on the River Thames for the 2010 election and political figures in the studio for the 2015 election. He has also provided commentary on foreign elections, and with Katty Kay led the BBC's overnight live coverage of the 2016 United States presidential election. In the run-up to the General Election in 2017 he interviewed five of the party Leaders on BBC One in The Andrew Neil Interviews.

Neil married Susan Nilsson on 8 August 2015. He had dated the Swedish civil and structural Engineer for several years. Nilsson is currently Director of Communications of engineering and environmental consultancy Waterman Group Plc. By 2006 he had 14 godchildren but he has no children of his own.

Neil earned £200,000 to £249,999 as a BBC presenter in the financial year 2016–17.

As of 2018 Neil presents live political programmes This Week on BBC One and Daily Politics on BBC Two. He was the Editor of The Sunday Times for 11 years. Neil is the former editor-in-chief and current chairman of the Press Holdings group, which owns The Daily Telegraph and The Spectator.