Massa had already driven one farewell race, thinking he was waving goodbye to F1 after 250 starts at the end of last season.
However, the move of Valtteri Bottas to replace retired world champion Nico Rosberg at Mercedes saw Williams rush the Brazilian back into his seat just weeks after he had vacated it.
He was handed a one-year deal and was under consideration for an extension at Williams.
But he handed Williams a deadline of the Brazilian Grand Prix, his home race and the penultimate event of the season, which they could not meeting, forcing him to retire.
“With the timing of it all, Felipe needed a decision before Brazil,” Williams boss Paddy Lowe told Motorsport.com.
“We weren’t able to.
“He was still in the running and was a strong candidate.
“But we weren’t able to make that commitment at that point.
“So we agreed that he would drop out of considerations and retire from the team.”
Massa’s second retirement has left a sought-after gap in the market, with any number of unemployed racers looking to take his place.
Williams appear to have whittled the number down to three, with Robert Kubica and Russian pair Sergey Sirotkin and Daniil Kvyat thought to be the final candidates.
And Sirotkin has emerged as the favourite for the seat after impressive times during testing in Abu Dhabi.
He is also backed by around £15million of sponsorship although Kubica is now thought to have tabled a similar but smaller offer in an effort to win the seat.