In a filing to US regulators, he said he also disagreed with some "strategic decisions" made by the company.
The exact nature of the disagreements was not detailed.
But Mr Murdoch has previously criticised News Corp outlets, which include the Wall Street Journal, for climate change coverage.
Rupert Murdoch, News Corp's executive chairman, and his other son Lachlan, co-chairman, wished James well in a joint statement.
"We're grateful to James for his many years of service to the company," the statement said. "We wish him the very best in his future endeavours."
Representatives of Mr Murdoch and his wife Kathryn have acknowledged the couple's "frustration" with coverage of the subject by some of most influential Murdoch-owned news brands, including Fox News.
They have also spoken of particular disappointment about climate change denial in Murdoch-owned Australian outlets.
News Corp also owns The Times, The Sun and The Sunday Times in the UK, as well as a stable of Australian newspapers, including The Australian, The Daily Telegraph and The Herald Sun.
James Murdoch's resignation letter:
This is business….if you want a friend, buy a dog.