Mandle began his career as an associate director of the Minneapolis Institute of the Arts before moving on to direct the Toledo Museum of Art. As deputy director and chief curator of the National Gallery of Art in Washington, DC, from 1988-93, he was an outspoken arts activist and oversaw all aspects of managing the respected museum. While in the capital, Mandle served as a member of the National Committee for Education Standards in the Arts and helped write the position paper Education Goals 2000: Standards in the Arts. Both President Ronald Reagan and President George H.W. Bush appointed him to the National Council on the Arts, one of scores of policymaking and advisory groups he has served on and led over the years.

In 1993, Mandle accepted the presidential position at The Rhode Island School of Desing in Providence, RI. During his tenure at RISD, Mandle oversaw the development of several ambitious projects and is often credited for driving down acceptance rates and transforming RISD into an elite institution. He is also credited for initiating several programs with nearby Brown University included a dual-degree program which allows students to earn a B.A and a B.F.A from both institutions. In 2008, after 15-years at RISD, Mandle stepped down from his post, leaving the position to John Maeda.

After leaving his post at RISD in July 2008, Mandle assumed the directorial position at the Qatar Museums Authority (QMA).