The husband-and-wife team beat England team-mates Sam Walker and Tin-Tin Ho 3-0 in the final.
"We had no expectations coming into it, really, other than just wanting to enjoy it," said Jo Drinkhall.
"I think we came together better than ever, it really felt natural."
Find out how to get into table tennis with our special guide.
Paul Drinkhall won his sixth men's singles title by beating Walker 4-2 in Nottingham, while Ho beat Kelly Sibley 4-2 in the women's final.
Drinkhall and Liam Pitchford won the men's doubles, and Ho and Maria Tsaptsinos took the women's title.
Paul and Jo Drinkhall won England's National Championships mixed doubles title as they returned to competition for the first time since winning Commonwealth gold at Glasgow 2014.