In 2001, Osmeña was one of the senators who voted in favor of opening the second bank envelope for the impeachment case filed against Joseph Estrada. The motion was outnumbered, and it led to the second EDSA People Power Revolution. He ran as independent for the position of Senator under the People Power Coalition. He won in the elections and served his second term as senator from 2001-2007. Right after Senator Aquilino Pimentel Jr. was replaced by Senator Franklin Drilon as Senate President, he joined Pimentel's party PDP–Laban. His mandate as senator for the second term expired in 2007.