Lepage was raised in Quebec City. At age five, he was diagnosed with a rare form of alopecia, which caused complete hair loss over his whole body. He also struggled with clinical depression in his teens as he came to terms with being gay.
Between 1975 and 1978, he studied theatre at Quebec City's Conservatoire d'Art Dramatique. He subsequently participated in workshops at Alain Knapp's theatre school in Paris, France.
After coming back to Quebec City, he wrote, directed and played in a few independent productions and joined Théâtre Repère in 1980. With that company, he created Circulations (1984), which was presented across Canada and won an award as best Canadian production during La Quinzaine Internationale de Théâtre de Québec. The following year, he created The Dragons' Trilogy and immediately received international recognition. Vinci (1986), Polygraphe (1987–1990) and Tectonic Plates (1988–1990) followed and were also toured around the world.
He was the artistic director of the National Arts Centre's Théâtre français in Ottawa from 1989 to 1993, and continued to stage plays. His productions of Needles and Opium, Coriolanus, Macbeth, The Tempest and A Midsummer Night's Dream were all created in that period.
In 1994, Lepage founded Ex Machina, a multidisciplinary production company, for which he is artistic director. Lepage and Ex Machina have toured numerous productions internationally to critical and popular acclaim, most notably The Seven Streams of the River Ota (1994) and Elsinore (1995). Lepage was invited in 1994 to direct August Strindberg's A Dream Play at Royal Dramatic Theatre in Stockholm, Sweden. It premiered in the fall of 1994 and guest played in the spring of 1995 in Glasgow Scotland. Geometry of Miracles (1998) and The Far Side of the Moon (French: La Face cachée de la lune, 2000), a solo show in which he juxtaposed the Cold War competition of the Americans and the Soviets in the Space Race with the story of two Québécois brothers—one straight, one gay—and their competitive relationship after their mother's death. It went to win numerous awards, including four trophies at le Gala des Masques, a Time Out Award and the prestigious Evening Standard Award. The Far Side of the Moon was adapted by Lepage—who plays both brothers—into a critically acclaimed 2003 film of the same name.
Lepage has directed five other feature films: The Confessional (Le Confessionnal) (1995), Le Polygraphe (1996), Nô (1998), Possible Worlds (2000) and Triptyque (2013) (the latter co-directed by Pedro Pires), and has acted in films by other directors, notably Jesus of Montreal (Jésus de Montréal) (1989) and Stardom (2001) by Denys Arcand. He has also been involved in music productions, being the stage director for the Secret World Tour by Peter Gabriel in 1993/1994, and the subsequent Growing Up tour in 2003/2004. He directed a number of operas, including Bluebeard's Castle and Erwartung at the Canadian Opera Company, The Damnation of Faust in Japan and Paris, and Lorin Maazel's 1984 at the Royal Opera House in London in 2005. Finally, Cirque du Soleil asked him to create the permanent Las Vegas show named Kà at the MGM Grand in 2005.
The Andersen Project is his last solo play inspired by the life and works of Danish writer Hans Christian Andersen and his tale "The Dryad"; it received many international prizes and, after being presented by Lepage himself in more than ten countries, is currently starring Yves Jacques who did the same in the past for The Far Side of the Moon.
Lipsynch, his large-canvas work, premiered in its first version in Newcastle upon Tyne's Northern Stage in February 2007 in its 5-hour version; it is now 9 hours long. He also staged Igor Stravinsky's The Rake's Progress, which was presented in Brussels' Opéra de la Monnaie in April 2007 and San Francisco War Memorial Opera House in November 2007.
Recent projects include The Image Mill, celebrating the 400th anniversary of Quebec City. For forty nights, residents and visitors could see the biggest outdoor architectural projection ever made in the world. In forty minutes, Lepage and Ex Machina celebrated four centuries of human and materiel development right where the river narrows, on the banks of Bassin Louise, using the huge surface of the Bunge grain elevators as a giant screen. More than an historic tableau, The Image Mill is a light-hearted and lively illustration in three dimensions of the city's past, present and future. It is a mosaic of icons, sounds and ideas covering four great epochs in the progress of Quebec City: 1) the age of waterways and exploration; 2) the age of roads and settlement; 3) the age of railroads and development; 4) the age of air travel and communication. The first presentation of this portrait of Quebec City took place at sundown on June 20, 2008, the evening of the summer solstice.
In November 2008, Lepage directed a staged version of Hector Berlioz' The Damnation of Faust at the Metropolitan Opera in New York. On February 25, 2009, Lepage premiered a new work entitled Eonnagata at Sadler's Wells Theatre, London, UK. He has worked on this alongside the dancers Sylvie Guillem and Russell Maliphant, fashion designer Alexander McQueen, lighting designer Michael Hulls and sound designer Jean-Sébastien Côté.
His production of Stravinsky's The Rake's Progress, conducted by Christopher Hogwood, was re-released at the Teatro Real, Madrid, in January 2009.
In spring 2009, Lepage presented The Blue Dragon (Le Dragon Bleu), a sequel to his Dragons' Trilogy, in which he reprised (more than twenty years later) the role of Pierre Lamontagne, a Québécois artist who lives in China.
In fall 2009, Lepage directed The Nightingale and Other Short Fables, an operatic staging of short works by Stravinsky blending hand shadow puppetry, Kabuki theatre, Chinese opera and Vietnamese Water puppetry. The Canadian Opera Company in Toronto premiered the work.
Lepage then wrote and directed Totem, Cirque du Soleil's next touring show, as well as on a new production of Der Ring des Nibelungen by Richard Wagner for the Metropolitan Opera of New York. The series was presented in installments during the 2010/2011 and 2011/2012 seasons – Das Rheingold and Die Walküre were premiered during the 2010/2011 season, Siegfried premiered on October 27, 2011, and Götterdämmerung premiered on January 27, 2012. Lepage's complete Ring cycle premiered in April 2012. The Metropolitan Opera had to install steel reeinforcements under the stage in order to support LePage's roughly 45 tonne stage. Lepage was featured in a 2012 documentary about the Met Ring production, Wagner's Dream.
In 2012, he appeared as a hologram in Martin Villeneuve's Mars et Avril, a science fiction film based on the graphic novels of the same name.
His autobiographical "memory play", 887 played in New York City (as "New York Critics Pick") and Toronto in 2017. In an associated interview, he calls himself a "lukewarm separatist".
In 1994, he was made an Officer of the Order of Canada "for his particularly imaginative and innovative work". In 1999, he was made an Officer of the National Order of Quebec. In 2001 he was inducted into Canada's Walk of Fame. He was promoted to Companion of the Order of Canada in 2009 "for his international contributions to the performing arts, particularly in film, theatre and opera, as an actor, producer and director".
On April 29, 2007, he was awarded the European Commission's Europe Theatre Prize for 2007. The honours were to be shared between Lepage and German stage director Peter Zadek, but Zadek did not show up and was not awarded the prize.
In 1994, Lepage received the National Arts Centre Award, a companion award to the Governor General's Performing Arts Awards. In 2009, Lepage received the Governor General's Performing Arts Award for Lifetime Artistic Achievement. He could not attend the ceremony but accepted the award via a pre-recorded speech.
He was nominated for the Genie Award for Best Achievement in Direction for his films Le Polygraphe, Possible Worlds, and Far Side of the Moon. He won the award for his film The Confessional (Le Confessionnal).
He was nominated for the Jutra Award for Best Direction for his film Nô. He won the Special Jutra Award for his film Possible Worlds.
In 2013, Lepage won the tenth Glenn Gould Prize, among whose former winners were: Leonard Cohen, Pierre Boulez, Oscar Peterson, Lord Yehudi Menuhin.