Murphy, who was acquired from the Washington Nationals in a trade Tuesday, will play second base and will hope to spark a lineup that has managed just five runs, all via solo home run, in its last five games.
Murphy will be followed in the lineup by Javy Baez, who will play shortstop, and Anthony Rizzo, who will play first base for the Cubs.
The Cubs are expected to use Murphy extensively at second base in the stretch run, with Addison Russell battling an injury and struggling mightily at the plate. He will split time there with Ben Zobrist, who will serve as the designated hitter on Wednesday night.
First pitch between the Cubs and Tigers is set for 6:10 p.m. at Comerica Park, with Jon Lester taking the hill for the Cubs.