ABC said a replacement for McPherson will be announced shortly.
McPherson's resignation from the top programming job at ABC comes just days before the network's presentation of its fall schedule to a meeting of TV reporters and critics.
The fall season begins in September, with ABC's schedule having been assembled by McPherson and featuring new series stars including Matthew Perry, Michael Imperioli, Michael Chiklis and Dana Delany.
When he started in 2004, McPherson had helped turn the network around after an over-reliance on "Who Wants to be a Millionaire" by his predecessors had severely cut into ratings and advertising revenues.
The Associated Press contributed to this report.