Despite concerns about the former Exxon Mobil CEO's ties to Russia, he won a 53-42 vote.
The South Carolina governor is the fourth confirmed cabinet member.
Representative Tom Price of Georgia faces a second Senate committee on his nomination for health secretary.
Perdue served on Trump's agricultural advisory committee during his presidential campaign.
Could ethical questions doom any of the president-elect's nominations?
U.S. President-elect Donald Trump has chosen pro-Russian Rex Tillerson for secretary of state.
Meanwhile, Donald Trump has been selected as “Time” magazine’s Person of the Year.
The new head of the Department of Health and Human Services could repeal the Affordable Care Act and restructure Medicare and Medicaid.