Marquez, fresh off a win in Argentina, won in 43min 57.945sec, with Yamaha rival Jorge Lorenzo second 6.107sec behind and Italian Ducati rider Andrea Iannone third 10.947sec back.
Two-time world champion Marquez also strengthened his hold on the top spot in the overall standings while nine-time world champ Valentino Rossi, who came into the race eight points behind Marquez, crashed out on his Yamaha.
With his second win of the 19-race season Marquez preserved a perfect record on US soil after starting first on the grid.
Another Spaniard, the reigning world champion Lorenzo, who like Yamaha team-mate Rossi has struggled on the track tucked into the hills outside the Texas capital, roared off the start line to seize the lead going into turn one.
But he went wide exiting the turn, allowing pole-sitter Marquez to move in front, and Ducati rider Andrea Dovizioso powered into second on the back straight as Spain’s Aleix Espargaro moved into fourth on his Ducati.
Rossi’s challenge ended on the third lap, when he lost the front end of his bike at turn two and crashed, his run of 24 races with a top-five finish ending.
Meanwhile Marquez and Dovizioso were separating themselves, Marquez building his lead to a second midway through the fourth lap.
Behind the Spaniard plenty of drama unfolded.
As Espargaro faded, Lorenzo got past Dovizioso with Marquez’s Honda team-mate Dani Pedrosa lurking behind.
But on the seventh lap disaster struck as Pedrosa lost control, his bike skidding outside and collecting Dovizioso — the second race in a row that Dovizioso was taken out by another rider.
Pedrosa briefly rejoined the hunt while Dovizioso’s day was done.
On the eighth lap Cal Crutchlow and Bradley Smith both fell off, rejoining in a frantic bid to salvage a point or two.
The falls promoted Iannone — who qualified fourth but started seventh because a penalty from the Argentina race — to third, a place he maintained to take his first points of the young season.
Marquez goes into the next race in Jerez, Spain, on April 24, atop the standings with 66 points. Lorenzo is second on 45 and Rossi third on 33.
“Of course I’m happy with this advantage that we have,” Marquez said. “OK, it’s only the third race, but we already have 21 points so this is really important for me and the team.
“The other riders made a few mistakes, but you must be there – and now in Europe we will see, because Jorge will be really strong.”
– Tyre decision key –
Marquez, in consultation with tyre manufacture Michelin, took a risk and went with a softer compound front tyre.
“Until lap 12 the tyre was perfect but after the race it was completely destroyed,” he said. “I knew it would be on the limit, but I tried to use this potential in beginning of the race, tried to open this gap.
“I kept pushing during all the laps because I didn’t know when the drop would arrive. When there were five laps to go, I start to feel a big close feeling at the front.”