[citation needed] Santoro was elected to the Legislative Assembly of Queensland as Liberal member for Merthyr in Brisbane from 13 May 1989 until 19 September 1992.

He first contested the seat at the 1986 state election against Liberal-turned-National incumbent and Transport Minister Don Lane, and finished third on the primary vote.

Merthyr was abolished in 1992, and Santoro followed most of his constituents into the re-created seat of Clayfield, which he held from 19 September 1992 until he was defeated on 17 February 2001 by Liddy Clark.

[2] As a senator, Santoro was a strident critic of the Australian Broadcasting Corporation, using parliamentary privilege in 2003 to accuse the national broadcaster of "sloppy and shoddy" journalism, and disloyalty to Australian soldiers serving in Iraq, after an internal memo to ABC news staff instructed them to refrain from referring to soldiers as "our troops".

On 14 March 2007, Senator Santoro disclosed that he had breached the government's ministerial code of conduct[4] by holding shares in CBio, a biotechnology company related to his portfolio.