The Hammers had been the better side at the Emirates Stadium and Michail Antonio had hit the crossbar having earlier levelled after Alexandre Lacazette’s 50th Arsenal goal had opened the scoring.
But manager Mikel Arteta took Lacazette off and replaced him with Nketiah, who was on hand to finish Dani Ceballos’ centre to secure a 2-1 win in this Premier League London derby.
There was a certain irony to the match-winning combination after Ceballos and Nketiah were involved in an altercation during the warm-up ahead of last weekend’s victory at Fulham.
This was another three points for the Gunners but there was little of the swagger and vigour that saw them easily brush Fulham aside last week.
Pierre-Emerick Aubameyang could not mark his first game since signing a new three-year deal with a goal but he did lay on the assist for Lacazette’s header.
West Ham, without injured captain Mark Noble, started the better of the two sides – David Moyes having them well-drilled for the task at hand.
Despite Arsenal’s slow start the visitors were unable to capitalise as Lacazette made the breakthrough with their first chance of the night.
Bukayo Saka, recalled in place of Ainsley Maitland-Niles, slid in Aubameyang and his cross was headed home by the France striker.
The goal was checked by VAR as Aubameyang looked like he may have just been offside as he collected the through ball but the goal stood.
Saka should have done better with his own opportunity to double the lead soon after but could only fire over the bar.
Moyes then appeared aggrieved as he watched back a replay of a VAR check for handball against Arsenal defender Gabriel Magalhaes, which was turned down.
West Ham did not allow their heads to drop and were level on the stroke of half-time as Antonio slid in to turn home a Ryan Fredericks low cross.
It would be West Ham who passed up a fine chance to take the lead early in the second half as Antonio miscued his effort from almost point-blank range after good work from Arthur Masuaku.
They came even closer in the 66th minute as Antonio this time headed against the crossbar with Bernd Leno seemingly beaten.
With the game seemingly slipping out of Arsenal’s grip, Arteta turned to Nketiah off the bench.
The striker had hit a hat-trick as he captained England’s Under-21s to victory over Kosovo earlier this month and he would prove the difference here.
Saka played a fine ball into the path of Ceballos who, after a quiet afternoon, was calm enough to square for Nketiah – who did the rest.
Starting the season with back-to-back wins would have been seen as crucial for Arteta, whose side now face Liverpool, Sheffield United, Manchester City, Leicester and Manchester United in their next five league games – all clubs that finished above Arsenal last season.
For West Ham, there was much more here for Moyes to take away as opposed to their tepid display in defeat to Newcastle on the opening weekend but he will be keen to get points on the board sooner rather than later.