Police and firefighters were called to Mason Street, south of the city centre, at about 8.30pm on Friday.
Firefighters entered the property wearing breathing equipment and rescued two young children.
Despite giving advanced life support to both children, they were pronounced dead at the scene, West Midlands Police said.
Two other children and a woman had already left the property before emergency services attended.
They were checked over by paramedics but did not require hospital treatment.
Police have erected a cordon around the scene while work is done to establish a cause for the fire. It is expected to remain in place for some time.
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