After quitting the Velvets, he reemerged as a solo performer in England, where he was adopted by admirers such as glam rock pioneer David Bowie (Bowie, David), who produced and performed on his breakthrough hit, "Walk on the Wild Side" (1973), and Mott the Hoople, who covered Reed's Velvets' classic "Sweet Jane." Later Patti Smith (Smith, Patti) and Television's Tom Verlaine would cite him as an inspiration for the mid-1970s New York City punk scene (see ). Yet, all the while, Reed flirted with self-parody and self-destruction, through drug and alcohol abuse and a string of wildly erratic recordings and concerts. His albums embraced everything from rote pop to heavy metal and included an orchestrated song cycle about a sadomasochistic love affair, Berlin (1973), and a double album of guitar drones, Metal Machine Music (1975), that are among his most notorious works. Onstage, his image and appearance changed yearly, from a leather-bondage-wearing ghoul feigning heroin injections to a deadpan guitar-strumming troubadour.

At the onset of the 1980s, Reed recruited his finest post-Velvets band, including guitarist Robert Quine and bassist Fernando Saunders, and reimmersed himself in raw guitar rock on The Blue Mask (1982), addressing his fears, ghosts, and joys with riveting frankness. No longer bedeviled by his addictions, Reed adopted a more serious if less daring tone on his recordings, peaking with three releases that were less concept albums than song cycles: New York (1989), about the spiritual death of his hometown; Songs for Drella (1990), an elegy for his 1960s mentor, Pop art conceptualist Andy Warhol (Warhol, Andy), done in collaboration with former Velvets bandmate John Cale; and Magic and Loss (1991), inspired by the deaths of two friends. A romantic relationship with American performance artist and musician Laurie Anderson (Anderson, Laurie) rejuvenated him again in the mid-1990s, resulting in the playful Set the Twilight Reeling (1997) and the harder-hitting Ecstasy (2000).

In 2000–01 Reed collaborated with director Robert Wilson to bring to the stage POEtry, a deconstruction of the work of Edgar Allen Poe (Poe, Edgar Allan). The songs from the show also were packaged on The Raven (2003), with spoken-word interludes—an ambitious if critically panned experiment. It was followed by Animal Serenade (2004), an excellent live recording that echoed Reed's landmark 1974 concert album Rock'n' Roll Animal. In 2006 Reed celebrated New York City in a book, Lou Reed's New York, which collected his photography.