The Scrubs star will join Rachel Nichols, Jean Reno, Matthew Fox and director-turned-actor Tyler Perry, who has taken the lead role originated by Morgan Freeman.
McGinley will play a fiery chief of police who finds himself on a constant collision course with Cross, a low-key sleuth, Showblitz reports.
I, Alex Cross sees Perry's character hunting a serial killer who he believes murdered his pregnant wife.
The film is an adaptation of James Patterson's crime series, with the main character younger than in the novels.
Director Rob Cohen is best known for helming The Mummy: Tomb of the Dragon Emperor and The Fast and the Furious.
Shooting is expected to begin later in August, with Cleveland substituting for Washington DC.
McGinley was most recently attached to Smothered, as one half of a pair of overbearing parents.
The pilot was dropped by ABC after the network decided against a midseason airing.
McGinley's film work includes several collaborations with Oliver Stone, including Wall Street, Platoon and Born on the Fourth of July.