In politics, McGuire was a prominent campaigner for Australian republicanism (the movement for replacing the Queen of Australia as Australia's head of state). He was elected as a delegate to represent Victoria at the 1998 Constitutional Convention, which led to the ultimately unsuccessful 1999 referendum. He is the brother of the Australian Labor politician Frank McGuire. Although being the brother of Frank McGuire, and having ties to Labor party members, ultimately Eddie McGuire stated in 1999 that he would be conflicted representing either the Australian Labor Party or the Liberal Party of Australia. He noted the confounding differences between the economic and social policies of each party and the irreconcilable dissonance in wanting to represent a Liberal Party styled economy with a Labor Party conscience. In 2002, McGuire stated he would not seek sanctum in politics, but that he would not say no to any future thoughts about the matter. McGuire was given the opportunity to represent the seat of Scullin by the Australian Labor Party in 2005, however, his business ventures were prioritised alongside McGuire becoming the then CEO of the Nine Network by 2006.