Perween Rahman, the director of the Orangi Pilot Project, was on her way home Wednesday night when she was shot and killed by gunmen on a motorcycle, said a police officer.
She was struck four times in the chest and neck and died on the way to the hospital, he said.
Rahman was an architect who left private practice early in her career to help the poor.
The Orangi Pilot Project operated in the squatter slums that make up a huge part of Karachi.
The innovative project, started in the 1980s, helped residents of those poor communities build their own sewer and water systems.
The port city, a sprawling metropolis of 18 million, is made up of a mish-mash of essentially illegal land settlements where poor people purchased land from developers and built their homes.