A major crash in Melbourne's CBD in which a tram collided with a car, causing the tram to jump off the tracks and ram two other vehicles, may have been triggered by a driver running a red light, police say.

A car driving south on Queen Street smashed into the tram heading east on Collins Street just before 1am on Friday.

The 25-year-old driver was trapped inside her vehicle until firefighters were able free her from the wreckage, an MFB spokeswoman said.

Paramedics took the Mornington woman, who suffered a head injury, to the Royal Melbourne Hospital where she remains in a serious condition.

When the tram derailed it ran into a taxi and a ute, but no one else was injured.

The exact circumstances of the crash have not been established, but police are investigating whether the woman ran a red light, a police spokeswoman said.