In 1992, Ople ran for the Senate under the Laban ng Demokratikong Pilipino (LDP) and won, placing No. 11 in the 24-man winning state. He served for six years with his co-winners in the top 12. The lower 12 served for three years. He was elected Senate President Pro Tempore in October 1996. He was reelected in same post in July 1997.

In 1998, he ran for reelection under the ticket of the Laban ng Makabayang Masang Pilipino (LAMMP) and won, placing seventh.

In the Senate, he chaired the Senate foreign relations committee and served as a member of the Commission on Appointments. He became acting Senate President with the resignation and death of Senate President Marcelo Fernan. In July 26, 1999 he was elected by his colleagues as the President of the Senate and served until July 12, 2000.