Weisz was born on 7 March 1970 in Westminster, London, and grew up in Hampstead Garden Suburb. Her father, George Weisz, was a Hungarian Jewish mechanical engineer. Her mother, Edith Ruth (née Teich), was a teacher-turned-psychotherapist originally from Vienna, Austria. Her parents emigrated to the United Kingdom as children around 1938, prior to the outbreak of World War II, in order to escape the Nazis. Her maternal grandfather's ancestry was Austrian Jewish; her maternal grandmother was Catholic and of Italian ancestry. The scholar and social activist James Parkes helped her mother's family to leave Austria for England. Weisz's mother was raised in the Catholic church and formally converted to Judaism upon marrying Weisz's father. Weisz's maternal grandfather was Alexander Teich, a Jewish activist who had been a secretary of the World Union of Jewish Students. Her younger sister Minnie Weisz is a visual artist.

Weisz's parents valued the arts; they encouraged their children to form opinions of their own by engaging their participation in family debates. Weisz left North London Collegiate School and attended Benenden School for one year, completing A-levels at St Paul's Girls School. Known for being an "English rose", Weisz began modelling at the age of 14. In 1984, she gained public attention when she turned down an offer to star in King David with Richard Gere.

In 1992, Weisz appeared in the television film Advocates II, followed by roles in the Inspector Morse episode "Twilight of the Gods", and the BBC's steamy period drama Scarlet and Black, alongside Ewan McGregor. Dirty Something, a BBC Screen Two, hour-long television film made in 1992, was Weisz's first film.

Weisz's breakthrough role on the stage was that of Gilda in Sean Mathias's 1994 revival of Noël Coward's Design for Living at the Gielgud Theatre, for which she received the London Critics' Circle Award for the most promising newcomer. Her portrayal was described as "wonderful" by a contemporary review.

Weisz started her film career with a minor role in the 1994 film Death Machine; her first major role came in the 1996 film Chain Reaction. The film received mostly negative reviews–it holds a 16% rating on Rotten Tomatoes and was a minor financial success. She next appeared as Miranda Fox in Stealing Beauty, directed by Bernardo Bertolucci, where she was first labelled an "English rose". Weisz found roles in the 1997 American drama Swept from the Sea, the 1998 British television comedy-drama My Summer with Des, Michael Winterbottom's crime film I Want You, and David Leland's The Land Girls, based on Angela Huth's book of the same name.

In 2000, she portrayed Petula in the film Beautiful Creatures, followed by 2001's Enemy at the Gates, and the 2002 comedy-drama About a Boy, with Hugh Grant, based on Nick Hornby's 1998 novel. In 2003, she played Marlee in the adaptation of John Grisham's legal thriller novel The Runaway Jury; and starred in the film adaptation of the romantic comedy-drama play The Shape of Things.

In 2004, Weisz appeared in the comedy Envy. The film failed at the box office. Variety opined that Weisz and co-star Amy Poehler "get fewer choice moments than they deserve." Her next role was alongside Keanu Reeves in Constantine, based on the comic book Hellblazer. Film Threat called her portrayal "effective at projecting scepticism and, eventually, dawning horror".

Weisz starred in the film The Whistleblower, which debuted at the Toronto International Film Festival in 2010. The film was based on the true story of human trafficking by employees of contractor DynCorp. During its première, the intense depiction of the treatment meted out to victims by the kidnappers made a woman in the audience faint. Variety wrote "Weisz's performance holds the viewer every step of the way." That same year, she guest-starred in the animated series The Simpsons, in the 22nd season episode "How Munched is That Birdie in the Window?". Weisz's 2011 roles included an adaptation of Terence Rattigan's play The Deep Blue Sea, Fernando Meirelles' drama 360 the BBC espionage thriller Page Eight, and the thriller film Dream House.