Hamilton headed Lando Norris and George Russell at the end of the second hour of practice, with the Ferrari pairing of Carlos Sainz and Charles Leclerc next best.
Max Verstappen was only 17th, though Red Bull Racing ran a different program, using the soft tyres early and swapping onto the mediums throughout the rest of the session.
Conditions had cooled once more from opening practice, with the track temperature just 13 degrees, marginally above the late-night Las Vegas ambient.
All 20 drivers headed out in the opening minutes, and all on the medium compound tyres.
In Free Practice 1, Mercedes had topped the session. But while Russell and Hamilton had been towards the top of the timesheets throughout the session, their ultimate pace was put down to the timing of their final runs.
As Free Practice 2 began, the pair were towards the front again; Hamilton setting the running at 1:35.805s after 10 minutes.
Ferrari was also towards the top of the timesheets, Sainz the faster of the two in the initial running before Leclerc topped the session with a 1:34.605s.
Grip remained at a premium, especially so at the braking zone into Turn 14 where a number of drivers pinched a brake a skidded into the run-off.
In most instances, those who went off were locking the loaded front wheel, the front-right, as they battled for brake temperature.
The tight left-hander is at the end of the 1.9km back straight, during which the brakes lose temperature and grab in the cold conditions.
It wasn’t the only area of concern, with a host of drivers running wide at Turn 1 and around the Sphere at Turn 7.
Problems for Williams kept Alex Albon in the garage after the team found a fault in the fuel system of his car.
The squad had done well to not only repair its cars following a disastrous Sao Paulo GP, where two chassis were damaged, but to deliver them in Las Vegas with the latest spec components.
He was soon back out on track, but only briefly as, with just under 23 minutes remaining, the red flag was shown after he stopped on track at Turn 6.
“The team attempted to repair Alex’s fuel system and participate in the remainder of FP2, however the issue has persisted which unfortunately forced the car to stop on track,” the squad subsequently confirmed.
Prior to the stoppage, soft tyre runs through the middle part of the sessions offered an insight into the pecking order.
Mercedes remained rapid, though not quite as quick as Lando Norris who topped the session with a 1:33.836s.
Ferrari was also in the mix, though their pace was masked by remaining on the medium tyre as the others used softs.
However, some opted to perform their qualifying simulations following the Albon red flag, when the track have further evolved.
That left the likes of Kevin Magnussen in seventh place, ahead of Oscar Piastri, and Nico Hulkenberg in the other Haas in ninth.
Also muddying the water was Red Bull Racing not running a set of soft tyres as the others did, leaving their times outliers, hence Verstappen was only 17th fastest and Sergio Perez 19th.
Nonetheless, Mercedes performance was impressive, suggesting its Free Practice 1 pace was no flash in the pan and that the squad would be a factor for the balance of the weekend.
However, Ferrari and McLaren are close suggesting a tight top three.
Whether that is a top four with Red Bull Racing remains unclear, though it looks only fourth best based on the opening two hours of practice.
It was a better session for RB, with Yuki Tsunoda 10th fastest and Liam Lawson 15th, the latter’s best 1.8s away from Hamilton’s session topping 1:33.825s, though points this weekend look a long shot.
A final hour of practice remains in Las Vegas, starting at 18:30 local time on Friday (13:30 AEDT Saturday).
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