With Gabriel Jesus confirmed to be out for a few weeks with a hamstring problem, Nketiah will lead the line for the Gunners heading into the winter period, as was the case after the 2022 World Cup.
The England international impressed during Jesus's absence with a knee injury last year, and he has continued to elevate his game to new heights under Mikel Arteta, who started him alongside Bukayo Saka and Gabriel Martinelli for the visit of the Blades.
A compact Sheffield United were proving difficult to break down in the first half, but Nketiah made the difference in the 28th minute, controlling Declan Rice's pass with a silky touch to beat Auston Trusty before a calm finish low into the goal.
Nketiah's first strike of the afternoon saw the floodgates open, and as Wes Foderingham spilled a 50th-minute corner at the striker's feet, he quickly reacted to find the top corner and double his tally.
Only eight minutes later, the 24-year-old completed his hat-trick with one of the goals of the weekend, taking Emile Smith Rowe's pass on the turn and firing a ferocious postage-stamp effort past Foderingham.
Nketiah's maiden top-flight hat-trick comes nearly two years after his first treble for Arsenal in an EFL Cup win over Sunderland in December 2021, and the Hale End academy graduate paid tribute to his late aunt after the game.
"It's amazing. It's not been easy - last month I lost my auntie so I want to dedicate these three goals to her. Her family was here watching so it is a really special moment," Nketiah told BBC Sport's Match of the Day.
"These games are about patience, not losing discipline. For the first goal, it was a good ball from Dec and a lovely touch and finish from myself.
"The second, I thought it was clean to go but it is never nice when see the purple VAR screen turns up. The third was amazing, a great strike and a special moment."
Nketiah could very well have finished the game with four goals to his name, emulating Andrey Arshavin and Thierry Henry, as Arsenal were awarded a late penalty when Oliver Norwood chopped down Fabio Vieira.
However, the Englishman selflessly allowed Vieira to convert the penalty he won, and Nketiah admitted that he went against his first instinct as a striker to prioritise the wider team.
"My first instinct was to grab the ball and go, but Fabio won it and it was a good moment. It's all about being a team player. It was his time to get a chance and he tucked it away," Nketiah added.
Sheffield United had already entered damage limitation mode before a 10-minute added time period, where Takehiro Tomiyasu capped off a perfect afternoon for Arsenal with his first goal for the club on his 50th Premier League appearance.
The Gunners have now risen above Manchester City - who face Manchester United tomorrow - back into second place in the Premier League table, and they return to action on Wednesday for a third-round EFL Cup tie against West Ham United.