Amanda Bennett made the announcement on Wednesday one day after the Los Angeles Times said it would replace its editor.
Bennett gave no reason for her departure, but said: "I know it sounds platitudinous, but the fact is, you get to a point when it's time to leave."
Bennett did not say whether she was resigning or had been forced out. She said that she and Brian Tierney, the Inquirer publisher, "mutually agreed" that she would leave.
Los Angeles Times editor Dean Baquet said on Tuesday he was leaving after he resisted a plan by the paper's owner, Tribune Co, to cut more staff in a bid to save money at the struggling Los Angeles paper.
Baquet and Bennett's resignations come at a time when the US newspaper business is grappling with falling circulation as readers and advertisers move to the internet and other media.
Meanwhile, a dissident investor is escalating a showdown with the New York Times Co, seeking steps that would lessen the Sulzberger family's control over the storied newspaper company.
Morgan Stanley Investment Management, which owns 7.6 per cent of the company's stock and is unhappy with a long slide in its share price, submitted a proposal on Wednesday aimed at giving other shareholders more say in the company's operation and future.
The proposal calls on the Times' board to make several changes, including putting its dual-class share structure - which cements control of the company by the Sulzbergers - to a shareholder vote.
It also calls for the roles of chairman and publisher of the Times' flagship newspaper to be separated. Both jobs are currently held by Arthur Sulzberger Jr.