Thompson, who won the 2019 world title, was second in 800 metres on Sunday - the final event of the competition - but her personal-best time of two minutes 5.63 seconds was enough to take gold.
Johnson-Thompson finished with 6,740 points while Anna Hall of the United States, last year's world bronze medallist, captured the silver with 6,720 and Anouk Vetter of the Netherlands took the bronze (6,501).
Johnson-Thompson, who peered up at the scoreboard in joyous disbelief after the 800, ruptured her Achilles in 2020 and was forced to withdraw during the Tokyo Olympics when she tore a calf muscle during the 200m.
"This has been one of the most gruelling heptathlons I've ever done - the delayed start (Saturday, due to a thunderstorm), the long day, then I got about three hours sleep last night," Johnson-Thompson said. "But all these girls deserve such huge respect."
An exhausted Johnson-Thompson dropped to her hands and knees on the track and peered up at the scoreboard in joyous disbelief when the final results were posted.
World and Olympic champion Nafi Thiam of Belgium missed the event due to injury.
Johnson-Thompson's career was in doubt after she ruptured her Achilles in 2020. She has had several setbacks, including a torn calf muscle during the Tokyo Olympics 200m that forced her to withdraw.
She has said her goal is an Olympic medal in what will be her fourth appearance in 2024 in Paris. Her best finish was sixth in Rio in 2016.
She struggled to a disappointing eighth-place finish at the worlds last year in Eugene, but rebounded to capture gold at the Commonwealth Games in Birmingham. Her only other heptathlon since then was a second-place finish at the Hypo-Meeting in Gotzis, Austria in May.
Johnson-Thompson, who began working with new coach Aston Moore last summer, was well back in fifth place after three events on Saturday, but climbed into silver-medal position behind Hall with the fastest 200m to close Day One.
The British athlete overtook Hall with her leap of 6.54m in the long jump - the best in the competition - to open Day Two, and remained in the lead after the javelin.
Vuleta claims long jump gold with season's best jump
Ivana Vuleta of Serbia won the women's long jump at the World Athletics Championships on Sunday, soaring 7.14 metres, the best jump in the world this season. She secured the victory on her fifth of six jumps.
"It has been a long, long, long ride," Vuleta said.
"Every medal, every final is really special but at this age, it is really hard to keep everything together.
"I am glad that I have used all the experience I have, it was my greatest ally."
Vuleta won bronze at both the 2013 and 2015 worlds and at the 2016 Rio Olympics, where her medal was Serbia's first in athletics at the Games.
Tara Davis-Woodhall of the United States captured the silver on Sunday with a leap of 6.91m in her senior world championship debut, while Alina Rotaru-Kottmann of Romania jumped 6.88m for bronze.
"I knew I was ready and I will deliver in the right moment. Finally, I did something I was dreaming of for so long," Vuleta said.
"I am so emotional, this medal is really heavy. I enjoyed every single moment in this competition. After so many years and so many medals, I just knew I had to have one gold from an outdoor championships.
"The only gold missing is the one from the Olympic Games. With it, I will finish my mission in athletics."
Reigning Olympic and world champion Malaika Mihambo of Germany missed the competition due to injury.
Vuleta has traditionally had more success indoors, winning two world indoor titles. She was a disappointing seventh at the world outdoor championships last year in Eugene.
Cheptegei wins third successive 10,000m gold
Uganda’s Joshua Cheptegei delivered a devastating last lap to win a third successive World Championship 10,000 metres gold on Sunday despite barely competing over 25 laps in the last three years.
The world record holder over 5000m and 10,000m has had an injury-hit year and struggled to hit his top form but, on a hot, humid night in Budapest, he broke clear approaching the bell and stamped his authority over the field with a 53-second last lap to come home in 27:51.42.
Daniel Simiu Ebenyo of Kenya took silver with Selemon Barega of Ethiopia the bronze.
Katzberg takes shock hammer gold for Canada
Canada's Ethan Katzberg took a stunning World Championship hammer gold on Sunday with a massive national record throw of 81.25 metres in the fifth round.
Katzberg had smashed his personal best by more than two metres in qualifying and looked as if he could not believe he had triumphed in the final.
Poland's Olympic champion Wojciech Nowicki took silver with 81.02, with Hungary's Bence Halasz bronze in 80.82.
Pole Pawel Fajdek, seeking a sixth successive world title to match the record of pole vaulter Sergey Bubka, finished fourth.
