The vote came after Senate leaders agreed to resolve a dispute over Republicans' use of the filibuster to block executive department nominations.
Republicans Lamar Alexander and Bob Corker of Tennessee, Susan Collins of Maine, Mark Kirk of Illinois, John McCain of Arizona and Lisa Murkowski of Alaska joined Democrats in voting to end a filibuster and hold a floor debate on the nomination. A vote could come as early as Thursday evening, The Hill reported.
Sen. John Cornyn, R-Texas, said during Wednesday's debate Perez "has a record of ideological, polarizing leadership."
Sen. Marco Rubio, R-Fla., accused Perez of failing to answer questions during his confirmation hearings and said Republicans should disregard the deal on allowing up-or-down votes on some of President Barack Obama's nominees.
"We're being asked to vote to invoke cloture on the nomination of someone who has open contempt to a congressional subpoena," Rubio said.
"How can we possibly -- I don't care what deal was cut -- how can we move forward on someone who hasn't provided information asked for by a congressional committee?"
Sen. Tom Harkin, D-Iowa, said Perez has answered all question put to him by the Senate Health, Education, Labor and Pensions Committee.
Congressional Republicans have accused Perez, the outgoing head of the Department of Justice Civil Rights Division, of inappropriately intervening in a St. Paul, Minn., lawsuit seeking to limit fair housing claims.