Joe Mizzi commenced his political activities in the Youth section of the Malta Labour Party in 1975, where he was appointed as Propaganda Secretary.

In 1987 he contested the General Elections for the first time with the Malta Labour Party, and was elected to Parliament as a representative of the Second District, comprising of Cospicua, Vittoriosa, Senglea, Kalkara, Xghajra, Fgura and a part of Zabbar.

He subsequently contested the General Elections of 1992, 1996, 1998, 2003, 2008 and 2013, where he was elected each year. In 1989 he was appointed as Secretary of the Parliamentary Group and a Member of the Administration of the Malta Labour Party.

During the period 1996 – 1998 he was appointed Minister at the Office of the Prime Minister, with responsibilities for Police, Home Affairs, Telecommunications and Oil Exploration. In 1998 he was assigned the role of Shadow Minister for Environmental Planning and Oil Exploration.

In 2003 he was appointed as Shadow Minister for Infrastructural Services and Oil Exploration, which responsibilities also included Enemalta, Water Services Corporation, Telecommunications, the Malta Maritime Authority and MaltaPost, and in the period 2009 - 2011 he was Main Speaker for Transport, Resources and Oil Exploration, including the Malta Maritime Authority and Malta International Airport. In 2011 he was appointed as Main Speaker for Energy, Resources and Oil Exploration.

In 2013 he was appointed Minister for Transport and Infrastructure.