Rear Adm Sweeney held his post for two years from January 2017. "These are not normal times".
He is now the third senior Pentagon official to announce his resignation after President Donald Trump said U.S. forces would leave Syria. "It has been an honor to serve again alongside the men and women of the Department of Defense", Sweeney was quoted in a DoD statement.
Sweeney retired as a rear admiral in 2014.
While General Mattis had planned on remaining in the position until February 28 to allow for a "smooth transition", Mr Trump pushed for his early departure.
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The goalkeeper position is a different one but Simon, I could write a book about all the good things I could say about him. That's despite Dominic Solanke and Nathaniel Clyne both leaving the club yesterday and joining Bournemouth .
His resignation follows closely that of US Secretary of Defense James Mattis who stood down earlier this month after acknowledging policy differences with the US president.
Mr Mattis criticised the president upon leaving office, writing a letter that talked about "treating allies with respect" after the perceived betrayal of Kurdish allies in northern Syria.
Deputy Defence Secretary Patrick Shanahan is now Acting US Secretary of Defence.
General Mattis's departure coincided with the resignation of Chief Pentagon Spokeswoman Dana W White on Monday.
Trump's time in office has been plagued by a litany of high-profile resignations and firings within his administration, signifying a turbulent two years behind the White House doors.