The win was all the more satisfying given Ireland manager Martin O'Neill put out a completely changed starting XI from last Friday's disappointing Euro 2016 qualifier defeat to Scotland in Glasgow.
Shay Given came into goal to win his 127th cap. As expected, Derby County's Cyrus Christie made his debut at right-back while Alex Pearce partnered Ciaran Clark in central defence with Brady at left-back.
David Meyler captained the side from central midfield alongside Hull City team-mate Stephen Quinn with Pilkington and Antony Stokes on the flanks. Ipswich Town's striking tandem of Daryl Murphy and new cap David McGoldrick spearheaded the attack.
Though also missing many of his top players, US boss Jurgen Klinsmann fielded a far more experienced team, with six of his starting XI having played in the World Cup in Brazil last summer.
And though the Americans started the better, winning two early corners, the experimental Ireland side stole the lead with a delightful goal on seven minutes.
Pilkington linked well with McGoldrick who threaded a sublime return ball through for the run of the winger who finished well by dinking the ball over keeper Bill Hamid for his first goal on his eighth appearance for his country.
The US maintained their positive start, though, and they came within inches of levelling as Fabian Johnson shaved the outside of Given's left-hand post from Alejandro Bedoya's 23rd minute corner.
Defensive dithering by the visitors at the other end gifted Ireland a gilt-edged opportunity to double their lead four minutes later. As the Americans failed to clear, Murphy showed good skill to snatch possession in the area with Hamid having to race off his line to make a good save.
But some sloppy play by Ireland led to the US equalising on 39 minutes.
Ireland were stretched once Meyler's pass went astray in midfield. The counterattack was swift, culminating in skipper Jozy Altidore's cross being skilfully nodded down by Chris Wondolowski for midfielder Mix Diskerud to poke home.
The woodwork then prevented the US from taking a deserved lead into the break. Bedoya did well to pull the ball back from the end line on the right and Altidore crashed his shot off Given's crossbar.
Given was called on to make his first real save of the game six five minutes into the second half when parrying away a shot from Altidore with his feet.
A fine move down their right almost restored Ireland's lead three minutes later. Christie put Pilkington away with Murphy just failing to turn home the cross at the back post.
That lifted Ireland and they duly regained the lead three minutes later. Quinn did well to win the ball in the corner before another telling ball from McGoldrick put Brady in on goal to sweep home confidently.
Given made another top save on 67 minutes to keep Ireland in front when getting a vital touch with a foot to deflect substitute Bobby Wood's shot round a post.
The veteran keeper excelled again with a terrific save from another US substitute, Greg Garza, on 80 minutes before Ireland sealed the win two minutes later.
Shane Long initially burst forward to shoot against a post. The ball remained alive and fellow substitute McClean drilled a low shot to the net with the help of a deflection.
Brady then saved the best until last when he lifted a sublime free kick up and over the wall and into the top right-hand corner of Hamid's net for Ireland's fourth goal on 86 minutes.
Republic of Ireland: Given (Elliot 84); Christie, Pearce, Clark, Brady; Pilkington (McClean 64), Meyler, Quinn, Stokes (McGeady 59); McGoldrick (Long 77), Murphy (Hendrick 77).
USA: Hamid; Johnson, Cameron, Besler, Chandler (Morris 76); Beckerman (Ream 87); Bedoya, Diskerud (Rubin 76), Morales (Garza 64); Wondolowski (Wood 46), Altidore.
Referee: Pawel Raczkowski (Poland).