A third victory in four years at the Circuit of the Americas, with four-time champion German Vettel outside the top two finishers, would be enough for him to add a third title to those of 2008 and 2014.
That would place him alongside Australian Jack Brabham, Briton Jackie Stewart, Austrian Niki Lauda and Brazilians Nelson Piquet and Senna with three titles apiece.
The 30-year-old Briton has won nine races this year for a total of 302 points, a lead of 66 ahead of Vettel, who has won three times to accumulate 236 points in his first season with Ferrari.
Hamilton's Mercedes team-mate, German Nico Rosberg, who also has won three races, is third with 229 points, his challenge hit by retirements this year, notably in the Russian Grand Prix earlier this month when he led the race after starting from pole position.
"I'm going to take my time and work as hard as ever," said Hamilton. "My goal is to win a third title and until I achieve that there is no other goal. I feel incredibly fortunate to have this car.