The consumer products maker is the latest major sponsor, following PepsiCo and Anheuser-Busch, to show concern over the NFL's handling of domestic abuse allegations against several players.
Women make up 35 per cent of the average audience of 17.4 million during a regular-season NFL game and the league has made it a point to reach out to women in recent years.
The league has made Breast Cancer Awareness month in October a particular focus. Part of its NFL Pink "Crucial Catch" campaign, in partnership with the American Cancer Society, features players, coaches and referees wearing pink game apparel, on-field pink ribbon stencils, special game balls and pink coins.
P&G's Crest brand had been working on a program with players from each of the NFL's 32 teams to wear pink mouthguards and participate in other activities.
But on Friday the Cincinnati-based company said Crest would no longer be part of on-field activities and joined the chorus of sponsors voicing disapproval of the NFL's actions. It remains a sponsor but said it will "determine future actions as needed."
"The brand has decided to cancel on-field activation with NFL teams," said spokesman Paul Fox in a statement. "Domestic violence is completely unacceptable and we have strongly urged the NFL to take swift and decisive action to address this issue... Our decision to cancel this on field activity was related to this ongoing issue."
The company will still donate US$100,000 to the American Cancer society as planned and said breast-cancer awareness is a "critically important program to support women and their health."
The NFL said that the sixth year of the "Crucial Catch" program will proceed.
"We understand the ways the last week have impacted our partners, including Crest," the NFL said in a statement. "Players will still have the option to wear pink gear, including mouthguards, as planned, this year."
The league and its teams are under fire over their handling of several players with domestic violence allegations against them. An investigation has been launched into whether NFL commissioner Roger Goodell knew about or saw a video of former Baltimore Ravens player Ray Rice hitting his then-fiancee earlier than he said.
Most major sponsors have voiced disapproval, with Budweiser beer maker Anheuser-Busch saying it is "increasingly concerned" about the situation.
On Thursday PepsiCo CEO Indra Nooyi made a double-edged statement on the NFL's problems handling domestic violence, calling some players' behaviour "repugnant" while also noting that she believes commissioner Roger Goodell is "a man of integrity."
Manish Tripathi, assistant marketing professor at Emory University, said it's not yet clear whether P&G's move will be an isolated incident or open the floodgates for others.
"You're talking now about a specific promotion or campaign geared toward women," he said. "Anything that is negatively associated with NFL right now gets exacerbated with a campaign like that."
AP Writer Dan Sewell in Cincinnati contributed to report.