A seventh straight league victory for Northampton was achieved in devastating fashion with all four goals coming in the second half at the Matchroom Stadium.
Rod McDonald, Ricky Holmes and James Collins with two late strikes were the goalscorers as Town went 15 points clear of 4th-placed Wycombe Wanderers.
Speaking to his club's official website after the game, Orient player-boss Kevin Nolan was full of praise for the visitors.
"I thought Northampton were fantastic," he said.
"They showed us what it takes to get out of this division. They have come here, been efficient and brilliant in what they did and made us look ordinary in the second half."
Oxford United, currently third in League Two, will provide tough opponents for Northampton on Tuesday night but Chris Wilder's side will travel in confidence that they can beat any team in the division on their current form.