The former Pentagon general counsel will take office this week after a 78-16 vote, succeeding Janet Napolitano, who left in September to become president of the University of California system.
An array of former officials from Democratic and Republican administrations, including all three former department secretaries, endorsed Johnson. The relationships he built with Senate Republicans during his tenure at the Pentagon helped him win support while other presidential nominees have struggled to get to a vote.
He is now charged with overseeing one of the federal government's most unwieldy departments, which encompasses 22 disparate agencies, including those responsible for immigration, border security and airport security.
"There's no doubt that even on a good day, serving as secretary of the Department of Homeland Security is a really hard job," Sen. Thomas R. Carper (D-Del.), chairman of the Homeland Security Committee, said in a floor speech supporting the nomination. "Jeh Johnson, however, is no doubt up to this enormous task."
Nominated by President Obama in October, Johnson was the last of an initial batch of 13 nominees the Senate's Democratic leaders sought to clear in the last week under new rules that made it all but impossible for Republicans to use the filibuster to block executive and judicial branch choices.
The vote, with 16 Republicans opposed, reflected lingering resentment over the decision by Democrats to curtail the filibuster. Sen. John McCain (R-Ariz.) in particular has expressed disgust that Johnson could be confirmed without having to answer questions McCain had posed about border security issues.
After confirming Johnson, the Senate moved to begin considering a more controversial choice to be Johnson's deputy: Alejandro Mayorkas. The nomination of the former top federal prosecutor in Los Angeles, currently head of U.S. Citizenship and Immigration Services, has been held up for months over allegations that he intervened to fast-track visas requested by politically connected businesses. An investigation by the department's inspector general has not been completed, but officials said they had yet to find evidence of wrongdoing.
Senate Majority Leader Harry Reid (D-Nev.) said Monday that he hoped to call votes as soon as Wednesday on Mayorkas and other nominees, including Janet L. Yellen to be Federal Reserve chairwoman and John Koskinen to be Internal Revenue Service commissioner.
Any other nomination votes would occur after the Senate votes on the House-passed budget agreement and a defense authorization bill. Work on both is set to begin Tuesday.
Reid warned Republicans that continued delaying tactics could cause the Senate to remain in session through Christmas Eve, a prospect that nonetheless seems unlikely.