Three quarters of the region’s 54 MPs opposed the Withdrawal Agreement, as the government suffered a crushing defeat of 202-432.
Rother Valley’s Kevin Barron was one of only three Labour rebels to defy the party leadership and vote in favour of the deal.
Speaking on social media ahead of the Commons showdown, Mr Barron described Mrs May’s offer as “the only option that fulfils the promises I made to my constituents in Rother Valley and avoids the horror of a no deal Brexit”.
Rotherham MP Sarah Champion, who remained undecided until the final hours of the five day Brexit debate, eventually declared her opposition during a speech in the House.
“I want to support this deal,” she said, “but I cannot currently as it has fundamental flaws - not least, that it omits protections of workers’ rights”.
York Outer MP Julian Sturdy earlier surprised colleagues with a late change of heart as he branded the government’s plan a "leap of faith" and revealed that he could not support it in its current form.
Speaking late on Monday during the fourth day of Brexit debate, he said: "As it stands at the moment, the agreement is unacceptable."
He added that the backstop proposal that would kick in if no trade deal has been agreed by the end of the transition period in 2020 "risks placing our country at a significant disadvantage in negotiations on a comprehensive trade agreement with the EU".
Of the 12 Yorkshire MPs that swung behind the Prime Minister, 11 were Tory loyalists, including ministers Graham Stuart, Andrew Jones, Stuart Andrew and Rishi Sunak, as well as Chief Whip Julian Smith.
In the aftermath of the vote, Normanton, Pontefract and Castleford MP Yvette Cooper urged Mrs May to secure an “immediate extension of Article 50”, while Wakefield MP Mary Creagh led calls for a so-called People’s Vote.