She crossed the line in 12.59 seconds, repeatedly yelling "oh my God" as she pulled up in realisation of her achievement.
Harrison - who was the 1/6 on favourite for the title and had not been beaten in a race since the US Olympic trials previous year - at least made it unlike Jamaica's defending champion Danielle Williams who flopped to finish fifth in her semi.
Pearson's problems started in 2015 when she broke her wrist in a race fall in Rome at the Diamond League event.
She then powered away in the second half of the race to take gold in 12.59sec, holding off another veteran American Dawn Harper Nelson (12.63sec), who'd relegated her to second in the 2008 Olympic final.
"I've worked so hard, I don't know what has just happened out there".
"I love this stadium, I love the people and I'm so happy to be back here doing the same thing again".
"I can not believe it, it's insane", said Dutkiewicz. I am glad I caught this moment of complete flow, of complete concentration.
Germany's Pamela Dutkiewicz claimed the bronze in 12.72 and Harrison trailed home in fourth place.
The 30-year-old's sublime run contrasted sharply with America's world record holder Kendra Harrison who squeaked into the final as the slowest of the two fastest losers who qualify.
Pearson, racing in lane three outside Harrison, blasted from the blocks and showed all her experience to concentrate on her own race as Harrison faltered.
The race was over as a contest as Pearson hurdled impeccably to hit the line in 12.53sec a broad grin spreading across her face and then clenched her fists in celebration.
Meanwhile, local favourite Mo Farah had to settle for a silver medal as he was beaten to 5000 metres gold by Muktar Edris in his final major championship race.
"Me and Sally have just battled it out for years and it's been so great to be here with her", Harper Nelson said.
Defending champion Danielle Williams of Jamaica failed to make the final while last year's Olympic champion Brianna Rollins, who led an American sweep of the Rio podium, is banned for a doping violation.