The Scuderia was in control throughout the session with a composed car over the few remaining Circuit of The Americas bumps.
Both Sainz and Charles Leclerc were rapid throughout the practice hour, the latter topping the timesheets on the hard compound rubber in the first 30 minutes.
He would likely have stayed there on the soft tyre runs too were it not for a late Virtual Safety Car which compromised his lap.
Max Verstappen was third best from Lando Norris and Oscar Piastri, while Liam Lawson was a promising 13th.
The Circuit of The Americas has been resurfaced since was last at the venue following complaints of excessive bumps in 2023.
There are other changes too, with grass added in some areas in an attempt to minimise – or eliminate – track limits issues.
As a Sprint weekend, the practice session was the team’s only opportunity to understand their cars, with eight of them carrying upgrades.
That included title protagonists Red Bull Racing and McLaren, the latter with seven listed components.
Promising early pace from both Ferrari drivers saw Leclerc head Sainz midway through the session, the pair split by two-tenths.
Leclerc’s 1:34.966s left him the better part of half-a-second clear of George Russell in third, though the Mercedes looked an edgy car, especially on the bumps.
Performance running began courtesy of Red Bull Racing, with Verstappen the first to bank a soft tyre time, a 1:33.855s to go fastest.
It was a time almost nine-tenths better than his team-mate Sergio Perez, who was only the better part of 30-second behind the Dutchman on track.
Verstappen held the same gap to Sainz on the Hard tyre, the Spaniard having inched ahead of Leclerc to set an identical time to Perez despite the difference in tyre compound.
Another lap from Perez saw the Mexican improve by a tenth to sit a clear second at the time, though still short of where he should have been relative to the rest of the pack.
With an extensive upgrade package, neither Norris nor Piastri showed their hand in the opening stages as the pair instead worked on assessing the upgrades, including a front wing that was fitted to both cars.
After half an hour, Piastri was the better placed of the two McLaren drivers, 1.3s off the outright pace.
Norris did improve in the latter stages of the longer run phase, though it was far from a representative time.
Meanwhile Piastri had a near miss on pit entry, narrowly avoid crashing into the barrier as he pushed the limits heading in.
He swerved right at the last moment and rejoined the track, catching the eye of officials, who gave him a black and white flag for ‘failing to follow race director’s instructions’.
On track, the Virtual Safety Car was briefly deployed, hindering Leclerc’s build-up lap as he looked to start his qualifying simulation.
Sainz had gone fastest with a 1:33.602s, marginally quicker than the compromised Leclerc once the Monegasque driver finally got to complete his lap.
Verstappen’s earlier effort saw him slip to third, with Norris slotting in fourth with his flying lap – the McLaren running wide at the end of the back straight to lose time.
Hamilton ended the session an encouraging sixth, his best time set on a used set of tyres.
Perez meanwhile was only 16th and a second off the pace, while Lawson was 13th best and just little more than a tenth down on RB team-mate Yuki Tsunoda.
The Kiwi had a quiet opening to the session before becoming one of the first to begin a performance run which saw him inside the top five for a time.
Elsewhere, Franco Colapinto had a number of moments as the rear stepped out and he opened the steering.
However, his exploits were nothing like the spin Hamilton suffered after his Mercedes bottomed out at Turn 4.
It pitched the seven-time champion sideways and into a wild spin after he was forced to enter the corner slightly narrower than usual as he passed a Haas on corner entry.
As the car bottomed out on the bump at corner entry, Hamilton became a passenger.
George Russell had a similar moment, though didn’t spin the car, moments later, though the second Mercedes driver did have a spin on the exit of Turn 1 soon after.
Pierre Gasly had spun the orange-for-the-weekend-Alpine too, his pirouette at Turn 1 coming earlier in the left-hander.
At the foot of the timesheets, Zhou Guanyu failed to complete a performance run as he struck trouble in the latter stages and saw his session end in the garage.
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