Officials confirmed seven people had died and health workers reported scores more were injured.
A 150-metre span of the eight-lane steel and concrete bridge, which carried a major road into Minneapolis, buckled and fell into the river and on to concrete embankments about 20 metres below.
Dozens of rescue vehicles rushed to the scene, and rescue divers were already in the water.
Television footage showed dozens of vehicles scattered and stacked on top of each other amid the rubble.
Some people were stranded on parts of the bridge that were not completely in the water.
Local stations also captured video of injured people being carried up the riverbank.
Gregory Wernick drove over the bridge shortly before the collapse, saved by his decision to stop for a drink nearby. He went back after hearing the commotion.
"I figure I crossed about 10 minutes before it happened," he said. "That's just too close to call. I've never seen anything like this."
Russ Knocke, a department of homeland security spokesperson, said there were "no indications of a nexus to terrorism at this time".