Officials at the Gay & Lesbian Alliance Against Defamation will bestow their Vanguard Award on Barrymore, while gay comedienne Wanda Sykes will receive the Stephen F. Kolzak Award at a glitzy gala in Los Angeles on 17 April (10).
Barrymore's honour comes after she portrayed Robert De Niro's lesbian daughter in Everybody's Fine, which has also been nominated for Outstanding Film at the event.
She has become a big favourite of GLAAD in recent years for her activism towards gay rights and joined thousands of marriage equality advocates on the streets of West Hollywood when the California Supreme Court upheld Proposition 8, which eliminated marriage for gay and lesbian couples.
The thrilled star says, "I was born, bred and raised among diversity, it has defined me and made me the person I am today. I'm honoured and humbled to be receiving this award."
Past recipients of The Vanguard Award include Charlize Theron, Antonio Banderas, Sharon Stone and Elizabeth Taylor.
Sykes' honour is annually presented to openly lesbian, gay, bisexual or transgender media professionals who have made a significant difference in promoting equal rights for the gay community.