Eventual race winner Max Verstappen's aggressive start in Mexico saw him take the lead from Hamilton's chief title rival Sebastian Vettel on the outside of the first corner, though there was contact between the pair.
Hamilton then found a gap to squeeze ahead of Vettel but the pair collided, causing damage to the German's front wing and a puncture to the Briton's rear tire.
Both had to pit at the end of lap one, with Vettel undergoing a nose change and Hamilton a tire change.
So in a bizarre turn of events, after four laps of the race, the two world championship title challengers were last and second last.
Vettel and Hamilton gradually moved up the field but the German had left himself too much to do to take his world title challenge to the season's penultimate race in Brazil.
"Honestly it doesn't feel real," said Hamilton of winning his fourth F1 title. "It was a horrible way to [clinch the title] to be honest, but what could I do?"
Ahead of Sunday's race, most thought claiming the world championship in Mexico was little more than a formality for Hamilton given his points lead in the drivers' title race, but just to make matters interesting the Mercedes car had struggled for pace in the altitude compared to Vettel's Ferrari in qualifying.
Verstappen had initially broken the track record to take pole position, but a blistering run from Vettel meant he would start from the front of the grid.
It was Vettel's 50th pole of his career, joining Hamilton, Schumacher and Ayrton Senna as the only drivers to reach the half century mark.
In an interview before the race, Verstappen was asked about the start of the Singapore Grand Prix six weeks ago in which he and Vettel collided before the first corner -- putting a huge dent in the German's title hopes -- and whether the same could happen again in Mexico.
"We have learned from our mistakes," was Verstappen's reply.
Except in Sunday's frenetic start there was contact between the pair again, though it was nothing like the carnage in Singapore.
"Simply, simply lovely," Verstappen said, admiring his handiwork, while Hamilton asked his team about the collision with Vettel: "Did he hit me deliberately?" "I don't know, Lewis," was the reply.
While Vettel gradually began to fight his way through a congested field, Hamilton remained in last place and appeared unable to get anyway near Carlos Sainz Jr.'s Renault.
"I can't get close to a car," an exasperated Hamilton said over the team radio on lap 24.
To make matters worse, Hamilton was quickly blue flagged and overtaken by race leader Verstappen and teammate Valtteri Bottas.
It was the first time the 32-year-old had been lapped since the 2013 Spanish Grand Prix where he finished 12th.
Four laps later, Hamilton eventually passed Sainz but was soon relaying information to his garage that he was concerned about his tires lasting the duration of the race.
After 35 laps, Vettel found himself in eighth place, still a huge 63 seconds behind the second place he needed to keep his title hopes alive.
Conveniently for Hamilton -- though bad news for Vettel -- it was his Mercedes teammate Bottas who occupied that position.
Vettel, however, had just set the race's fastest lap and climbed to seventh to give him a glimmer of hope.
With 20 laps remaining, he then passed home favorite Sergio Perez with a brave, intricate move on the inside -- though it didn't go down well with the partisan crowd.
Vettel continued to set fastest laps and make his way through the field, finding himself in fifth and 50 seconds behind Bottas with 16 laps to go.
The German had at least made things interesting but, at this stage, would need a miracle to secure at least second place.
To make matters worse for Vettel, Hamilton had found some speed and began working his way up through the pack, eventually entering the points positions in 10th.
Hamilton eventually crushed any remaining hope Vettel had by brilliantly overtaking Fernando Alonso to take ninth place, leaving the German needing to win the race keep the world championship alive.
It was game over, ensuring Hamilton becomes the first driver to win a world championship after being lapped since James Hunt in 1976.
The Brit had previously said he wanted to win the title in style by standing atop the podium in Mexico.
The race didn't go as he would have dreamt it but he surely won't mind.
Hamilton is the 2017 world champion, allowing him to join Vettel and Frenchman Alain Prost on four world titles.
Britain's most successful ever driver is now only behind Argentine Juan Manuel Fangio's on five and Michael Schumacher, the all-time record holder on seven.