As a young boy, Weitz was a member of the Knickerbocker Greys, a long-standing New York City youth marching corps that has been in existence since 1881.

Weitz was born in New York City, the son of Actress Susan Kohner and Berlin-born novelist/menswear designer John Weitz. His brother is filmmaker Paul Weitz. Weitz is the grandson of Czech-born agent and Producer Paul Kohner and Actress Lupita Tovar on his maternal side. Tovar, who was from Oaxaca, Mexico, starred in Santa, Mexico's first talkie, in 1932, as well as a Mexican version of Drácula. Weitz' paternal grandparents escaped Nazi Germany, before which his grandfather was a successful textile manufacturer, with the family being intimates of Writer Christopher Isherwood and Actress Marlene Dietrich.

Weitz began his film career as a co-writer on the animated film Antz (1998). He followed this with work on various sitcoms such as Off Centre and the 1998 revival of the 1977 TV series Fantasy Island. In 1999, he and Paul directed and produced American Pie, which was written by Adam Herz, and became a major box office success. Weitz returned as executive Producer on the film's two theatrical sequels. In 2001, along with his brother, he co-directed his second film, the Chris Rock comedy Down to Earth.

Weitz has also occasionally worked as an actor, playing the lead role in the 2000 comedy film Chuck & Buck and a bland suburbanite in Mr. & Mrs. Smith.

In 2002, the Weitz brothers co-wrote and co-directed About a Boy, the Hugh Grant film based on the book by Nick Hornby. The film was originally set up at New Line Cinema with Robert De Niro producing, and the main character as an American. The brothers felt that it was important that the character is British. Inspiration came from the 1960 film The Apartment. They were nominated for an Academy Award for Best Adapted Screenplay.

In 2003, Weitz was hired to direct New Line Cinema's adaptation of the first book in Philip Pullman's His Dark Materials series, The Golden Compass, after approaching the studio with an unsolicited 40-page treatment. He was subsequently invited by Director Peter Jackson to visit the set of King Kong, in order to gain insight into directing a big-budget film and advice on how to deal with New Line. In 2005, Weitz announced his departure from the film, citing the enormous technical challenges involved, and the fear of being denounced by both the book's fans and detractors; he was subsequently replaced by British Director Anand Tucker. Tucker left the project in 2006 over creative differences with New Line, and Weitz returned to the director's chair after receiving a letter from Pullman asking him to reconsider.

In 2004, Weitz was a co-investor with Paul Devitt in the Japanese restaurant and club called Tokio on N. Cahuenga in Los Angeles.

The film was released in 2007 and was met with mixed reviews. Its U.S. grosses have been described as disappointing in relation to film's $180 million USD budget, although it was a "stellar performer" outside the U.S. with a "stunning" box office likely to hit $250 million. When questioned about a possible sequel, New Line studio co-head Michael Lynne said that "The jury is still very much out on the movie..." The second and third screenplays have been written but because of the economic recession and the protest by the Catholic Church, the two sequels never got made. Its worldwide box office gross stands at $372,234,864.

In December 2008, Weitz was announced as the Director of the sequel to Twilight, the film adaptation of the novel New Moon by Stephenie Meyer. Weitz said he felt a tremendous sense of responsibility to live up to the expectations of the passionate fan base.

The Twilight Saga: New Moon opened in November 2009, one year after the first movie was released. New Moon set records as the biggest midnight opening in domestic box office history, grossing an estimated $26.3 million in 3,514 theatres, previously held by Harry Potter and the Half-Blood Prince. The film grossed $72.7 million on its opening day domestically, becoming the biggest single-day opening in domestic history, beating the $67.2 million tally of The Dark Knight.. This opening strongly contributed to another record: the first time that the top ten films at the domestic box office had a combined gross of over $100 million in a single day.

In June 2011, Summit Entertainment released his film A Better Life, written by Eric Eason about a Hispanic gardener and his son in Los Angeles searching for their stolen truck. This film is unusual among Hollywood productions in that it is set in a Hispanic community and features an almost entirely Hispanic cast. Weitz said that working on the film allowed him to explore his Hispanic heritage—his grandmother is from Mexico—and learn Spanish. The film was nominated for an Oscar.

In 2012, he worked with Journalist Jose Antonio Vargas on a series of four documentary shorts directed by Weitz called Is This Alabama?, about the effects of the state of Alabama's anti-immigration legislation, 2011's Alabama HB 56. The project was a collaboration between Weitz, Vargas, the Center for American Progress think-tank, America's Voice Education Fund, and Vargas' Define American campaign, with Vargas doing the interviews.

Weitz wrote a young adult novel trilogy series that began with The Young World, in 2014, and The New Order, in 2015. Weitz said that he used the concept of natural intelligence theories called Society of Mind created by Marvin Minsky to create the stories that were loosely autobiographical about growing up in New York City.

Weitz wrote the screenplay for Disney's 2015 live-action adaptation of Cinderella, which was released in theaters on March 13, 2015. Weitz said he went back to the many different versions of the story (Brothers Grimm, Charles Perrault, as well as the 1950 animated Disney original) as well as his own vision.

On November 11, 2016, after Donald Trump won the presidential election, Weitz tweeted, "Please note that the Empire is a white supremacist (human) organization." Although he had apologized and deleted the tweet, several Trump supporters have used the hashtag #DumpStarWars and claimed that Rogue One contained an anti-Trump scene.