Zverev's win marked his return to the Miami Open semifinals for the first time since his runner-up finish in 2018
Victory for the Briton's Mercedes team mate Nico Rosberg in Mexico will see the German become champion with two rounds to spare if Hamilton has another stroke of bad luck and finishes outside the top nine.
Rosberg, who has a 26 point lead, won at the Autodromo Hermanos Rodriguez last year - qualifying on pole and setting the fastest race lap - immediately after Hamilton had wrapped up the title in Texas.
He could repeat the feat but, despite nine victories so far in 2016, Rosberg has yet to win this season without Hamilton finishing at least seventh and more usually on the podium.
Hamilton is also in a very different state of mind to this time last year and not about to settle for anything less than another win.
"The moment you give up is the moment you lose," said the champion, who can join French great Alain Prost on 51 wins and equal second on the all-time list of grand prix winners behind Michael Schumacher (91).
"I've never been one to give up and I don't plan on starting now. There are still plenty of points available and anything is possible."
Hamilton finished runner-up in Mexico last year when the country returned to the calendar for the first time in 23 years.
The altitude and slippery surface made the race more challenging while one of the biggest crowds of the year produced a memorable atmosphere.
"Even though last year's race was a bit frustrating for me, I actually had a lot of fun out there. I'm looking forward to giving it another go and hopefully going one better this time," said the Briton.
Rosberg, still determinedly taking one race at a time, said he would be keeping it simple again.
"Standing on that podium last year was one of the best moments of my career, so I hope I can get back up there and experience it again," said the driver, whose father Keke was champion in 1982.
Reliability is the big concern for both, despite Mercedes having already won the constructors' title for the third year in a row with 16 wins in 18 races and all but one pole position.
Hamilton lost out on 25 points in Malaysia when his engine failed while he was leading comfortably and that trauma has not gone away.
The Mercedes pair also have to worry about resurgent Red Bull, with Australian Daniel Ricciardo third in Austin and Dutch teenager Max Verstappen pushing hard until he retired with a gearbox problem.
Mexican fans now have two home race drivers to cheer on, with Force India's Sergio Perez joined by Esteban Gutierrez, still chasing his first points of the season, in the Haas.
Zverev's win marked his return to the Miami Open semifinals for the first time since his runner-up finish in 2018
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