Irishman Doherty, once a world number two but ranked 31st these days, had not beaten former world number one Higgins in a ranking tournament for seven years until Tuesday.
The match was a cagey encounter, with several frames coming down to the last few balls. Indeed, Doherty won the opening frame by clearing from brown to pink, while Higgins missed the brown off the last red as he lost the second.
Higgins pulled one back after Doherty missed the final green, but Higgins did likewise off the yellow in the fourth, with the Irishman winning thanks to a break of 46 in the fifth - the highest of their session.
"It was a war of attrition, there was a lot of good safety. You have to match John in every department and I beat him with my safety game today," Doherty, 43, told World Snooker.
"I have been starved of winning matches against the top players so it's a great result for me. I'm in the twilight of my career but there's still a bit of sparkle.
"It's like a rare fruit that you find now and then and it still tastes sweet. It gives me a real boost of confidence. People think I'm just a pundit now so it's nice to show I can still play."
In the last 16 Doherty next faces the winner of Ricky Walden's match with Tom Ford.
World number three Neil Robertson also required just five frames to overcome Ian Burns.
The Australian secured breaks of 78 and 71 to take the opening two frames, with Burns unable to respond.
A break of 76 saw the Preston player grab a frame back, but it did little to prevent Robertson from surging away to clinch victory.
Breaks of 85 and 70 were enough for the 31-year-old to close out the match in convincing fashion.
Stephen Maguire recorded a century break as he beat Anthony Hamilton in his first-round match.
The world number six began the match with a commanding break of 89, before Hamilton produced a century break to level up the scores.
The world number 37 moved in front in the third frame, but the century break and scores of 73 and 66 ensured Maguire’s progress.
Maguire now faces Matthew Stevens, who beat Liang Wenbo 4-2 later in the day.
"I have played Anthony a few times this season and he has beaten me," said Maguire.
"He's a great player and he was scoring heavily at the start. It was a good match for the first four frames and then we both struggled."
First round results:
Neil Robertson 4-1 Ian Burns
Stephen Maguire 4-2 Anthony Hamilton
Matthew Stevens 4-2 Liang Wenbo
Sam Baird 4-0 Gerard Greene
Mark Allen 4-2 Marco Fu
Ken Doherty 4-1 John Higgins
Pankaj Advani -3 SHaun Murphy
Alan McManus 4-2 Barry Hawkins