The Pirates of the Caribbean star tops the Entertainment Weekly list with editors insisting the quirky actor is such a big star he can "do anything he wants".
Excluding cameo and animated roles, the magazine estimates Depp's films have chalked up $5.9 billion globally.
Lady Gaga is second on the new list, thanks in part to her 5.1 million album sales in the past two years.
Talk show queen Oprah Winfrey comes in third, while Simon Cowell and Will Smith round out the top five.
Robert Downey, Jr., Sandra Bullock, Leonardo DiCaprio and Eminem also make the top 10.
Meanwhile, in a linked poll, Sam Worthington and Harry Potter star Daniel Radcliffe have been named the Highest-Grossing Movie Stars Under-40.
Aussie Worthington tops the list because his three leading films - Avatar, Clash of the Titans and Terminator Salvation - have earned a total of $1 billion, making his box office average $349.6 million (£233 million).
Radcliffe comes in second thanks mainly to his Harry Potter success - the 21 year old's box office average is $244.7 million (£163.1 million). Twilight stars Taylor Lautner and Robert Pattinson also make it into the top five, as does Will Smith's teenage son Jaden.
Orlando Bloom, Shia LaBeouf, Tobey Maguire, Hayden Christensen and Worthington's Avatar co-star Zoe Saldana round out the top 10.