In flashbacks, the audience is shown a young Margaret Roberts working at the family grocer's shop in Grantham, listening to the political speeches of her father, whom she idolised – it is also hinted that she had a poor relationship with her mother, a housewife – and announcing that she has won a place at Oxford University. She remembers her struggle, as a young lower-middle-class woman, to break into a snobbish male-dominated Conservative Party and find a seat in the House of Commons, along with businessman Denis Thatcher's marriage proposal to her. Her struggles to fit in as a "Lady Member" of the House, and as Education Secretary in Edward Heath's Cabinet are also shown, as are her friendship with Airey Neave, her decision to stand for Leader of the Conservative Party and eventual victory, and her voice coaching and image change.
Further flashbacks examine historical events during her time as Prime Minister, after winning the 1979 general election, including the rising unemployment related to her monetarist policies and the tight 1981 budget (over the misgivings of "wet" members of her Cabinet – Ian Gilmour, Francis Pym, Michael Heseltine, and Jim Prior), the 1981 Brixton riot, the 1984–1985 UK miners' strike, and the bombing in Brighton of the Grand Hotel during the 1984 Conservative Party Conference, when she and her husband were almost killed. We also see (slightly out of chronological sequence) her decision to retake the Falkland Islands following the islands' invasion by Argentina in 1982, the sinking of the ARA General Belgrano and Britain's subsequent victory in the Falklands War, her friendship with U.S. President Ronald Reagan and emergence as a world figure, and the economic boom of the late 1980s.
By 1990, Thatcher is shown as an imperious but aging figure, ranting aggressively at her cabinet, refusing to accept that the "Poll Tax" is unjust, even while it is causing riots, and fiercely opposed to European integration. Her deputy, Geoffrey Howe, resigns after being humiliated by her in a cabinet meeting, Heseltine challenges her for the party leadership, and her loss of support from her cabinet colleagues leaves her little choice but reluctantly to resign as Prime Minister after eleven years in office. A teary-eyed Thatcher exits 10 Downing Street for the last time as Prime Minister with Denis comforting her. She is shown as still disheartened about it almost twenty years later.
Eventually, Thatcher is shown packing up her late husband's belongings, and telling him it's time for him to go. Denis' ghost leaves her as she cries that she actually is not yet ready to lose him, to which he replies "You're going to be fine on your own... you always have been" before leaving forever. Having finally overcome her grief, she contentedly washes a teacup alone in her kitchen.
Meryl Streep as Margaret Thatcher
Alexandra Roach as young Margaret
Jim Broadbent as Denis Thatcher
Harry Lloyd as young Denis
Iain Glen as Alfred Roberts, Margaret's father
Emma Dewhurst as Beatrice Roberts, Margaret's mother
Victoria Bewick as Muriel Roberts, Margaret's sister
Olivia Colman as Carol Thatcher
Anthony Head as Sir Geoffrey Howe
Nicholas Farrell as Airey Neave
Richard E. Grant as Michael Heseltine
Susan Brown as June, Margaret's live-in carer
Martin Wimbush as Mark Carlisle
Paul Bentley as Douglas Hurd
Robin Kermode as John Major
John Sessions as Edward Heath
Roger Allam as Gordon Reece
David Westhead as Reg Prentice
Michael Pennington as Michael Foot
Angus Wright as John Nott
Julian Wadham as Francis Pym
Nick Dunning as Jim Prior
Pip Torrens as Sir Ian Gilmour
Nicholas Jones as Admiral Sir Henry Leach
Alexander Beardsley as young Mark
David Rintoul as Admiral Sir John Fieldhouse
Matthew Marsh as Alexander Haig
Phoebe Waller-Bridge as Susie, Margaret's Secretary
Ronald Reagan (archive footage) as himself
Reginald Green as Ronald Reagan