Heller said in a statement Monday that backing the proposal "is the right thing to do" and that his decision came after consultations with a wide range of Nevadans.
"This legislation raises the federal standards to match what we have come to expect in Nevada," Heller said.
Nevada is one of roughly 20 states that have bans on workplace discrimination based on either sexual orientation or gender identity.
Heller becomes the fifth Republican to publicly back the bill, which would impose a federal ban on workplace discrimination based on sexual orientation or gender identity. Nevada's junior senator has been the target of an intense lobbying push by gay rights and liberal groups who have sought to get the measure passed by the Democratic-controlled Senate.
Formal debate on ENDA could begin as early as Monday evening in the Senate, but some aides cautioned it might be delayed if not enough senators return to Washington in time for evening votes.
Regardless of whether the bill passes in the Senate, the GOP-controlled House appears unlikely to even vote on it.
The office of House Speaker John Boehner (R-Ohio) said in a statement Monday that Boehner remains opposed to the bill -- a position he has made clear before -- saying it would lead to "frivolous litigation."
“The speaker believes this legislation will increase frivolous litigation and cost American jobs, especially small business jobs," Boehner spokesman Michael Steel said.
In response, House Democrats quickly criticized Boehner for blocking the legislation and said that "all options will be on the table" in order to earn a vote in the House.
"It is deeply disappointing to see that Speaker Boehner would block any legislation that would end discrimination," said Drew Hammill, a spokesman for House Minority Leader Nancy Pelosi (D-Calif.). "But after spending $2.3 million in taxpayer dollars on a failed effort to defend discrimination against LGBT couples in federal courts, no one should be surprised."
But Hammill wouldn't say what options might be considered to force a vote in the House.
Updated at 1:43 p.m. Aaron Blake contributed to this post.