The president, his wife Michelle and daughters Sasha and Malia left their rental home on the island under steady rain and took a helicopter to a Coast Guard air station at Cape Cod, where they boarded their flight to Andrews Air Force Base outside the US capital.
From Andrews, the family boarded another helicopter for the short ride to the White House, arriving at 0257 GMT on Monday.
Earlier in the day Obama played golf -- his sixth round of the vacation -- with partners who included World Bank President Jim Yong Kim.
Obama interrupted his rest last week to denounce the bloody crackdown in Cairo by Egypt's military.
The president received regular intelligence briefings, and both National Security Advisor Susan Rice and Deputy Chief of Staff Rob Nabors were on the trip, White House spokesman Jay Carney earlier told reporters.
A favorite summer spot for the well-heeled, Martha's Vineyard is located off the coast of Cape Cod, Massachusetts, and has hosted the likes of ex-president Bill Clinton and late first lady Jackie Kennedy Onassis.
From 2009 to 2011, Obama spent about 10 days there each August, enjoying golf, picnics on the beach and eating out locally. He skipped a visit last year as he campaigned for re-election.
Obama's last vacation, over Christmas, was compromised by the so-called fiscal cliff fight with Congress, which forced the president to cut short his stay in Hawaii and head back to Washington.
The coming weeks for Obama are expected to be dominated by showdowns with opposition Republicans in the US Congress.
Turmoil in Egypt and the upcoming G20 summit in Russia are likely to take a backseat to the domestic agenda, as Republican legislators are threatening a government shutdown in October over the budget and debt ceiling.