At the age of 19, Milian signed a contract with Def Jam. In 2001, Milian released her self-titled debut album, which featured the singles "AM to PM" and "When You Look at Me"; "AM to PM" charted with in the Top 40 of the US Billboard Hot 100 and both peaked in the top three on the UK Singles Chart. In 2004, Milian released her second studio album It's About Time, which provided her first major US hit. "Dip It Low", which reached number 5 on the US Billboard chart, "Whatever U Want" was released as the album's second single, both singles charted within the Top 10 of the UK chart.
In 2006, Milian released her third studio album So Amazin'. The album produced one single, "Say I", which peaked in the Top 30 of the US Billboard chart. A month after the release of So Amazin', Milian's representative confirmed that she had left Island Records due to creative differences. Milian signed with Interscope Records in 2009. A single, ballad "Us Against the World", was released in October 2008. In 2012, Milian signed to Young Money Entertainment, which will release her fourth studio album.
Although Milian is best known for her singing career, she originally wanted to be an actress. Her first lead role was in the 2003 film Love Don't Cost a Thing, and she subsequently had main roles in Be Cool and the horror film Pulse.