He attended high school at the North Carolina School of The Arts, initially focusing on painting. He soon ventured into photography and developed a unique analogue technique of hand-painting his negatives, resulting in a sublime and rich spectrum of colors when processed.

In the 1980s, LaChapelle moved to New York. His talent caught the attention of Andy Warhol, who offered him his first photography job at Interview Magazine. LaChapelle's celebrity portraits garnered widespread acclaim, propelling him to shoot for prestigious editorial publications and create memorable advertising campaigns. His staged tableaux, portraits, and still-life works challenged conventional techniques and quickly gained international recognition.

LaChapelle's striking images have graced the covers and pages of renowned publications such as Vogue, Vanity Fair, GQ, and Rolling Stone. His portfolio includes portraits of the most influential media figures, including Tupac Shakur, Madonna, Eminem, Andy Warhol, Leonardo DiCaprio, Hillary Clinton, Jay-Z, Britney Spears, and Lady Gaga.

His solo museum exhibitions have been hosted at prestigious venues such as the Barbican in London, the National Portrait Gallery in DC, the Los Angeles County Museum of Art, the Museum of Contemporary Canadian Art in Toronto, Kunsthaus Wien in Vienna, Palazzo Reale in Milan, Musée de La Monnaie in Paris, and the Taipei Museum of Contemporary Art in Taiwan.