It is the top award available through the US National Institutes of Health (NIH) High Risk, High Reward Research Programme, and amounts to $US700,000 ($NZ1.117million) a year, for five years.
Prof Knight (43) is a professor of pediatrics at the University of California San Diego School of Medicine.
He also directs the UC San Diego Centre for Microbiome Innovation.
The award would make a "transformative difference" to his research, he said yesterday.
The funding would enable his research to move in a new direction - understanding at the molecular level how food and its transformation by microbes could prevent infectious disease.
A resulting focus on new technology development would benefit research in human health, agriculture and conservation, he said.
Born in Dunedin, Prof Knight attended Otago Boys' High School, later gaining a BSc in biochemistry from Otago University before gaining a PhD scholarship at Princeton University, in the US.
He is an international leader in research into healthy microbiomes.