Loveline began in 1983 as a Sunday night segment on Los Angeles radio station KROQ, hosted by DJ Jim "Poorman" Trenton and DJ Swedish Egil (Egil Aalvik). About a year later, Trenton added a segment called Ask a Surgeon, hosted by his friend Dr. Drew Pinsky, who was not yet a doctor but a fourth-year medical student at the University of Southern California. The two segments soon merged into their own show, co-hosted by Trenton and Pinsky. In February 1992, the show went from airing solely on Sunday nights to five nights a week (Sunday through Thursday). Over the years, Trenton's relationship with the station grew rocky, and in August 1993 he was replaced by former MTV VJ Riki Rachtman. Dr. Drew and Rachtman were joined by Adam Carolla in October 1995, just as the show was first being syndicated nationally. The trio hosted together for several months, but Carolla and Rachtman often competed for airtime, leading Rachtman to resign in April 1996. From that point, Adam Carolla and Dr. Drew hosted the show until Carolla's departure on November 3, 2005.

The popularity and reach of the show increased dramatically during the "Pinsky/Carolla" years. The two had a natural chemistry, in which Carolla's jocular tone emphasized Pinsky's reasoned expertise. Together, they refined the format of the show, and capitalized on their growing popularity with speaking tours, a television show, a book, and cameo appearances on television shows and in movies. Carolla left the show on November 3, 2005 to prepare for hosting a new morning radio show in 2006.

Loveline follows the call-in question-and-answer model with the primary goal of helping youth and young adults with relationship, sexuality, and drug addiction problems. As a practicing internist and addictionologist with training in psychology, Dr. Drew's answers have medical credibility, but the addition of Adam Carolla's humor and insight resulted in a program with entertainment value as well. Carolla repeatedly stated his role on the show as something of a trojan horse: He lured listeners with dirty jokes and wisecracks in hopes they'd learn something that could improve their lives. Actors or members of popular bands often participate as guests.

Since Carolla's departure in November 2005, the show has continued with celebrity co-hosts and guests, some of whom have announced their hope to be hired as Carolla's replacement. From July 23, 2006 through April 30, 2009, KROQ disc jockey Stryker served as co-host with Pinsky.

As of March 2010, KROQ's very own Mike Catherwood took over the co-hosting duties, bringing a unique viewpoint to the show as both a recovering addict and comedian.