Cross left after four years in the role saying fresh leadership was needed for upcoming "challenges and opportunities".
Natural England said that Marian Spain, who is a current board member of Natural England, would take over as interim chief executive "shortly" while a permanent lead is recruited. She has held a number of senior roles with organisations in the environment sector, including the Environment Agency and Countryside Agency – a predecessor body of Natural England.
Cross said: "We are now entering a new phase for Natural England, as we look forward to a new chair joining in January and begin preparations for the 2019 Spending Review.
"This follows a significant period of change, with the Countryside Stewardship/Environmental Stewardship transfer to the Rural Payments Agency on 1 October and the movement of a number of people through secondment and assignment processes.
"I feel it is the right time to allow fresh leadership of the organisation to tackle these challenges and opportunities. We have achieved a lot together since I joined back in 2014. I’m particularly proud of the network of marine conservation zones, the England Coast Path and pioneering new ways to connect people with nature through care farms and nature-friendly schools."
Natural England chairman Andrew Sells, who is due to retire in the New Year, said that Cross had been a key architect of important reforms which enabled Natural England "to secure significant gains for the natural environment through efficiency, innovation and collaboration in a difficult financial climate.
"James can take great pride in all he has achieved while chief executive and I wish him well in the future," he said.
Chief officer for strategy and reform, Alan Law, will work with Spain as her deputy.