The crash took place near Grand Avenue in the northbound lanes in Streeterville, Chicago fire officials said.
Two children were taken to Lurie Children's Hospital with minor injuries in good condition, officials said.
The driver suffered a medical emergency before losing control of the bus, Chicago police said. He later died at a hospital.
He was identified as 39-year-old Christopher Johnson by the Cook County Medical Examiner's Office. His exact cause of death was not immediately known.
Traffic was slowly getting around the crash just before 4 p.m.
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