Seacrest began his broadcasting career aged 16 while still in high school as an evening radio host for WSTR FM. Seacrest attended the University of Georgia, where he majored in journalism, and hosted an afternoon radio program on the Los Angeles radio station KYSR, Star 98.7, from 1995 to 2003.

Ryan's first television job was as a reporter for a weekend morning show created by CNET, that showcased new technology. Later he was a co-host, with MTV's Maria Sansone, of the syndicated Gladiators 2000. During college, Seacrest hosted ESPN's Radical Outdoor Challenge program; this led him to a series of television hosting jobs which culminated in the position as co-host of the hit reality TV series American Idol in 2002 with Brian Dunkleman. The following year, Seacrest became the sole host. In 2003, he also hosted the spin-off show American Juniors.

In January 2004, Seacrest launched a daily entertainment/variety/talk syndicated television program, On Air With Ryan Seacrest. However, due to low ratings, the show was cancelled and aired its last episode on September 17, 2004. Also in 2004, Seacrest created a new sign-off phrase for himself, "Seacrest . . . Out", with hopes that it would become a catch phrase. Unfortunately, it was so poorly received that both the catch phrase and Seacrest became the targets of derision and lampooning; in 2006 he stopped using it.

On January 10, 2004, Seacrest became the new host of the legendary radio program American Top 40, created and formerly hosted by Casey Kasem, syndicated by Premiere Radio Networks. Prior to taking over as host, Ryan was a substitute host four times in 2003 (during the final months of Kasem's tenure).

In February 2004, Seacrest became host of popular Los Angeles radio station KIIS-FM's morning show, replacing long-time host Rick Dees. This show, also named On Air With Ryan Seacrest, remains on the air.

In January 2005, Seacrest hosted the "Celebration of Freedom" concert in Washington, DC for President George W. Bush, the Bush family and the United States Military.

In late April 2005, Seacrest received a star on the Hollywood Walk of Fame at age 30 — unusually young for a non-child star; the honor is typically bestowed upon phenomenally successful performers in peak- or late-career stage.

In August 2005 it was announced that Seacrest would become executive producer and co-host of Dick Clark's New Year's Rockin' Eve, and that he would be the legendary producer-host's eventual successor. On December 31, 2005, Seacrest performed much of the show's hosting duties; Dick Clark's role was limited due to speech and mobility challenges in his recovery from a stroke.

Seacrest also occasionally serves as a substitute host on the cable television program Larry King Live.

In January 2006 U.S. cable channel E! announced a three-year/$21-millon deal for Seacrest to host and produce various programs, including its red carpet awards show coverages (E!'s signature piece of original programming). An AP profile portrayed Seacrest as using both this and the Dick Clark's New Year's Rockin' Eve involvement as a springboard towards a long-lasting career in television production and ownership. He continues to live in L.A.

Seacrest has his own line of designer clothes, called the R Line.

In March 2006, he was photographed kissing actress Teri Hatcher, but she later told Access Hollywood that she was "not attached."