Charlie Weber was born Charles Alan Weber Jr in Jefferson City, Missouri. Acting was something that Weber was always sort of involved in. He was interested in drama in high school, but he didn't really take part in school productions. After graduation, he went to college for one year, and decided that it wasn't for him, and wanted to see what was going on in the world, so he moved to New York City when he was 19 years old, that's when he began to study acting, he picked up a few modeling gigs to pay the bill before his acting career took off.
Weber made his screen debut in the 2000 film The Broken Hearts Club: A Romantic Comedy. Later in same year he was cast in the recurring role in The WB television series, Buffy the Vampire Slayer. he played the role of Ben, an intern who shared his body with female god Glory. He later guest-starred on The Drew Carey Show, Charmed, Veronica Mars, House, Burn Notice, Bones, Warehouse 13 and CSI: Crime Scene Investigation.
From 2003 to 2004, Weber had roles in films Gacy, The Kiss and Cruel Intentions, all movies received negative reviews from critics and was released direct-to-video. In 2010, he co-starred in the vampire-spoof film Vampires Suck. From 2003 to 2004 he had a recurring role of Jay in the another The WB drama series, Everwood. From 2012 to 2013 he appeared in the MTV comedy-drama series, Underemployed, and later had a recurring role on the fifth season of The CW teen soapy drama, 90210.
In March 2014, Weber landed a regular role as Frank in Shonda Rhimes' ABC legal drama series How to Get Away with Murder. As of June 2017, it was announced that Weber and co-star Liza Weil had been dating for a year.