Matt Langston, who works as a postman, scored the only goal of the game on Sunday in the 39th minute at a wet and wild Glassworld Stadium when he headed in Gareth Gwillim's cross.
It earned Histon a place in the third round and sent Leeds crashing to their first-ever defeat to a non-league team.
Leeds had the best chance of the opening exchanges when Luciano Becchio smashed Robert Snodgrass' cross wastefully over.
Histon striker Daniel Wright then went close at the other end but the hosts had the lead soon after.
Gwillim delivered a superb corner into the box and Langston thundered a header past David Lucas from eight yards for his first goal of the season.
Gwillim then denied Leeds substitute Enoch Showunmi before defender Lubomir Michalik rattled a Histon post after a goalmouth scramble.
Ten minutes later, Becchio flashed another great chance wide before Antonio Murray somehow cleared another Michalik shot off the line as Leeds laid siege to the goal but could not find an equaliser.