In the late 1990s, Miko returned to the United States and landed her first major film role in Coyote Ugly in 2000. This was followed with a lead role in the 2001 vampire horror film The Forsaken, playing a young woman infected by a vampiric virus. In 2005, Miko appeared in a multi-episode story arc on the HBO series Deadwood; the same year, she appeared in the music video for “Mr. Brightside” by The Killers (she would again collaborate with the band for the video of their 2012 single “Miss Atomic Bomb”, breaking her foot during filming). In 2006, she had a lead role in Save the Last Dance 2, replacing Julia Stiles from the original film.

In 2012, Miko appeared opposite Danny Huston and Sienna Miller in the period drama Two Jacks, directed by Bernard Rose, and in the South Korean dance film Make Your Move in 2013. Miko appeared in Billy Idol’s music video for “Can’t Break Me Down”, and also had a supporting role in Step Up: All In, both in 2014. Also in 2014, she had a small role in the TV show Supernatural, episode “Ask Jeeves” of season 10, where she portrays a shape shifter working for a rich heiress who has died. In 2015, Miko co-produced the biographical film Desert Dancer, which tells the story of Iranian choreographer Afshin Ghaffarian. The same year, she had guest appearances in the television series Blue Bloods and Scorpion, as well as a recurring role in the NBC action-drama series Chicago Fire.