Mr Wilke, 53, has been with Amazon for more than two decades and was regarded as a potential successor to founder and chief executive Jeff Bezos.
His oversight at Amazon grew along with the company, running not just Amazon.com, but the Whole Foods grocery chain and its physical book stores.
Mr Wilke is referred to within Amazon as “The other Jeff” to differentiate him from Mr Bezos.
He is simply one of those people without whom Amazon would be completely unrecognisable
The two have worked closely together since Mr Wilke joined the company in 1999, four years after Amazon.com started selling books online.
Mr Wilke will be replaced by Dave Clark, who runs Amazon’s warehouses and delivery network, the Seattle-based company said.
In an email to staff, Mr Wilke said he does not have another job lined up.
“So why leave? It’s just time,” he wrote in the email.
“Time for me to take time to explore personal interests that have taken a back seat for over two decades.”
Mr Wilke said he will focus on running the company through the holiday season, which is shaping up to be the busiest one yet for Amazon.
Sales have skyrocketed as online sales boom during the pandemic.
“He is simply one of those people without whom Amazon would be completely unrecognisable,” Mr Bezos wrote in a memo to staff.
“Thank you, Jeff, for your contributions and your friendship.”
