LuPone was born on April 21, 1949, in Northport, New York, on Long Island, the daughter of Italian-American parents Angela Louise (née Patti), a library administrator at the C.W.

[9] LuPone was part of the first graduating class of Juilliard's Drama Division (1968–1972: Group 1),[10] which also included actors Kevin Kline and David Ogden Stiers.

[12] According to LuPone, her rigorous Juilliard training has instilled in her "a respect for the craft of acting and the stage", but maintains that it did little to prepare her for the realties of pursuing a career on Broadway.

[22] In 1976, theater producer David Merrick hired LuPone as a replacement to play Genevieve, the title role of the troubled pre-Broadway production of The Baker's Wife.

[23] Since 1977, LuPone has frequently collaborated with David Mamet, appearing in his plays The Woods, All Men Are Whores, The Blue Hour, The Water Engine (1978),[24] Edmond, The Old Neighborhood (1997),[25] and The Anarchist (2012).

As Jolly, a part inspired by Mr. Mamet's real-life sister and his realized female character, Ms. LuPone finds conflicting layers of past and present selves in practically every line.

[27] In 1979, LuPone starred in the original Broadway production of Evita, the musical based on the life of Eva Perón, composed by Andrew Lloyd Webber and Tim Rice, and directed by Harold Prince.

[38] In May 1983, founding alumni of The Acting Company reunited for an off-Broadway revival of Marc Blitzstein's landmark labor musical The Cradle Will Rock at the American Place Theater.

[39] The production premiered at The Acting Company's summer residence at Chautauqua Institution, toured the United States including an engagement at the Highland Park, Illinois' Ravinia Festival in 1984 and played in London's West End.

In 1993, LuPone returned to London to create the role of Norma Desmond in the original production of Andrew Lloyd Webber's Sunset Boulevard at the Adelphi Theater.

[58] LuPone has performed in many New York concert productions of musicals including Pal Joey with Peter Gallagher and Bebe Neuwirth, Annie Get Your Gun with Peter Gallagher, Sweeney Todd with George Hearn in both New York and San Francisco, Anything Goes with Howard McGillin, Can-Can with Michael Nouri for City Center Encores!, Candide with Kristin Chenoweth, Passion with Michael Cerveris and Audra McDonald and Gypsy with Boyd Gaines and Laura Benanti for City Center Encores!.

[74][75] In August 2010, LuPone appeared in a three-day run of Irving Berlin's Annie Get Your Gun where she played the title role opposite Patrick Cassidy at the Ravinia Festival, directed by Lonny Price.

[76] That same year, LuPone created the role of Lucia in the original Broadway production of Women on the Verge of a Nervous Breakdown, which opened at the Belasco Theater on November 4, 2010, and closed on January 2, 2011, after 23 preview and 69 regular performances.

[79] In 2011, LuPone played the role of Joanne in a four-night limited engagement concert production of Stephen Sondheim's musical Company at the New York Philharmonic, conducted by Paul Gemignani.

[87] In early 2015, she returned to Los Angeles Opera to perform the role of Samira in a new production of John Corigliano's The Ghosts of Versailles, receiving positive reviews.

[95] Performing opposite Christine Ebersole as Rubinstein's longtime competitor Elizabeth Arden, LuPone stayed with the role for War Paint's entire run at the Nederlander Theatre, from March 7 to November 5, 2017.

"[98] Nevertheless, in September 2017 it was announced that LuPone would star as Joanne in the 2018 London revival of Company alongside Rosalie Craig as Bobbie in a gender-swapped production directed by Marianne Elliot.

A transfer of the successful West End production of Company was set to open at the Bernard B. Jacobs Theatre on March 22, 2020, coinciding with Stephen Sondheim's 90th birthday, but was postponed due to the COVID-19 pandemic.

On May 10, 2022, during a live conversation with the American Theatre Wing and her Company co-stars, Patti LuPone publicly addressed a patron who was not wearing their face mask properly, a violation of Broadway League COVID-19 safety protocols.

"[122] She also appeared as the inaugural act at the Sharon L. Morse Entertainment Center in The Villages, Florida on April 30, 2015, to a sold-out audience of residents mainly 55 years-of-age and older.

[128] In 2010, theatre critic Charles McNulty wrote that her stage presence demonstrates a ferocity that, when paired with the right material, resembles "a return to a golden age when powerhouses ruled Broadway".

[124] AllMusic biographer William Ruhlmann noted that, unlike her predecessors Mary Martin and Ethel Merman, LuPone was never afforded the luxury to seamlessly transition between musical productions, instead using lulls in her Broadway career to diversify her endeavors by appearing in plays, films, television, nightclubs, concert tours, and recording solo studio albums.

[130] At the same time, she has expressed frustration at frequently being overlooked for roles she believes she is best suited for, often in favor of less qualified actors,[126] and insists she has been bullied by Broadway professionals for much of her career.

[138] After undergoing surgery to treat vocal nodules during the 1990s,[139] she learned how to sing in a more operatic manner to preserve her voice, prior to which she admitted to relying on "sheer guts and willpower" to belt.

[55] According to Andrew Gans of Playbill, LuPone belongs to a handful of singing actors who "are masters of stillness, bringing songs to full life with an inner well of emotions that seep out in unexpected and heartbreaking moments".

[132] In addition to Sondheim, LuPone has identified performers Edith Piaf, Bette Davis, and David Mamet as influences,[147] and expressed admiration for stage actresses Angela Lansbury, Zoe Caldwell, and Elaine Stritch, all of whose signature roles she would eventually play herself.

[55] Theatre critic Ben Brantley reported that the fallout from Sunset Boulevard damaged LuPone's public image and relegated her Broadway appearances to one-woman and non-musical shows, until she returned to musical theater in the early 2000s.

[55] Her fanbase has been nicknamed "LuPonistas",[29][151][152] and she has often been hired to play exaggerated versions of herself in television and film, representing "the symbol of Broadway musical theater", according to Time Out's Adam Feldman.

[127] A vocal critic of the commercialization of Broadway, LuPone has likened its current state to Las Vegas,[13][132] [126][153] arguing that shows should have limited runs to allow space for fresh, innovative productions.

The couple's wedding ceremony was on the stage of the Vivian Beaumont Theater at the Lincoln Center on December 12, 1988, after filming the TV movie LBJ; Johnston was a cameraman.