Forbes magazine's list calculates the Pirates of the Caribbean star returned only $2.80 (Â£2.20) at the box office for every $1 (78p) he was paid for the last three films he made before June.
Those films include Alice Through the Looking Glass, which stumbled at the box office when it was released in May.
Will Smith is ranked second, returning $5 (Â£3.94) on every dollar.
The figures are based in part on his medical drama Concussion and the romantic comedy Focus.
But they do not factor in comic book movie Suicide Squad, which arrived in cinemas in August.
Channing Tatum is ranked third in the list, just ahead of comic star Will Ferrell.
The Anchorman star topped the list in 2009 and 2010 and was ranked third one year ago.
Each actor's ranking is based on the box office performance of the last three major films up to June 2016 in which they had a starring role.
Animated releases, films where the actor had in a minor role or those released on fewer than 2,000 screens are not used in Forbes' calculations.
The magazine then takes the estimated production budget away from the global box office returns for each film to work out each one's operating income.
That figure is then added to the estimated total fee for each star across their three films to discover the final figure for return on investment.
Depp's putative return is better than that of one year ago, when he was adjudged to have returned $1.20 (94p) for every $1 he was paid.
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Johnny Depp has been named the most overpaid actor in Hollywood for the second consecutive year.