In 1995, she formed the band Hush with Rade Popovi? (guitar, vocals), Milan Sari? (bass guitar) and Bojan Ivkovi? (drums). Hush performed rhythm and blues, but also incorporated elements of funk and soul into their sound. The band had their first performance in the club Vox in Belgrade. During 1996, Hush performed across Serbia, also performing in Greece. Thanks to their performance at the Marsoni Blues Festival in Senta, Hush got the invitation to perform at the Fifth International Blues, Jazz, Rock and Gastronomic Festival in Hungary. A part of their performance was released on a live album which featured recordings from the festival. In 1996, Popovi? played slide guitar on Piloti album Dan koji prolazi zauvek (The Day that Is Passing Forever).
During 1998, Hush had over 100 performances, playing in blues clubs and blues festivals. During the same year, they released their debut album, Hometown, through PGP-RTS. The album was produced by Aleksandar Radosavljevi?, and featured Vojno Dizdar (electric piano and Hammond organ), Petar "Pera Joe" Miladinovi? (harmonica), Aleksandar Tomi? (tenor saxophone) and Predrag Krsti? (trumpet) as guests. Beside the band's own songs, Hometown also featured covers of blues standards.
In 1999, Popovi? formed the Ana Popovi? Band in the Netherlands. In 2000, she appeared, alongside Eric Burdon, Taj Mahal, Buddy Miles, Double Trouble, Eric Gales and others, on the Jimi Hendrix tribute album Blue Haze: Songs of Jimi Hendrix with a cover of the song "Belly Button Window". In 2001, she released her solo debut, Hush!, through the German label Ruf Records. The album was recorded in Memphis, with the members of Ana Popovi? Band, as well as studio musicians. It was produced by Jim Gaines, who previously worked with Carlos Santana, John Lee Hooker, Alexis Korner and others. The album featured Bernard Allison as guest. The album saw large success, so Popovi? left her guitar studies, and dedicated herself to performing.
In 2003, Popovi? released her second album, Comfort to the Soul. The album, recorded in Memphis and produced by Gaines, featured a fusion of blues, rock, soul and jazz. During the same year, on the Rhythm & Blues Festival in Belgium, she was invited by Solomon Burke to join him on stage, after which she joined him on the rest of the tour as a guest. In 2005, Popovi? released a live album and DVD entitled Ana! Live in Amsterdam, recorded on January 30, 2005 on her concert in Amsterdam club Melkweg.
In 2007, Popovi? released the album Still Making History through the American record label Eclecto Groove Records. In 2009, she released the album Blind for Love, and in 2011 the album Unconditional through the same label. Both Still Making History and Unconditional reached number one in the United States Billboard Blues chart. In 2012, Popovi? moved to Memphis, Tennessee.
Popovi?'s ninth full-length album, entitled Can You Stand the Heat, was released in April 2013 through ArtisteXclusive records. The album, produced by Tony Coleman, was recorded with John Williams on bass guitar, Harold Smith on rhythm guitar, Frank Ray Jr. on organ and Tony Coleman on drums. Popovi? performed at the 2013 New Orleans Jazz & Heritage Festival, where she introduced a new project: a nine-piece band under the name Ana Popovic & Mo' Better Love. In September 2013, Popovi? signed with Monterey International booking agency.
Popovi? released a triple album titled Trilogy on May 20, 2016. The album includes multiple guests, including Joe Bonamassa, Robert Randolph, Cody Dickinson (North Mississippi Allstars), Bernard Purdie, and rapper Al Kapone.