Andriy Yarmolenko scored in the 29th minute to equal the record of Andriy Shevchenko for most goals in Yellow and Blue history and Roman Yaremchuk doubled the lead five minutes later.
Ezgjan Alioski cut the deficit in half with a 59th-minute strike, but it wasn't enough for the Lions, who are all but eliminated from advancing to the last 16 on their tournament debut.
Story of the match
North Macedonia had the first chance of the match as Alioski sent a lovely ball over the top which was just out of the reach of Eljif Elmas. At the other end, Lions goalkeeper Stole Dimitrievski punched away Ruslan Malinovsky's searching delivery.
With Ukraine slowly taking over the game, North Macedonia managed to counter as Elmas had a near-post flick, but it only touched the side netting. It would be on 29 minutes that the tournament debutants fell behind.
Yarmolenko managed to evade his amrker and squeeze the ball past Dimitrievski for a 1-0 lead and five minutes later, the West Ham United forward turned provider, sending a deft pass into the path of Yaremchuk, who doubled the Yellow and Blue advantage.
After halftime, North Macedonia began playing more aggressively as Aleksandar Trajovski saw his shot played onto the post by Ukraine goalkeeper Georgiy Bushchan, but Goran Pandev was subsequently brought down.
Alioski stepped up to take the penalty and although Bushchan guessed right and made the save, the Leeds United wing-back was quickest to the rebound and finished to make it a 2-1 game.
Dimitrievski denied Malinovsky from the penalty spot late on while Trajovski saw Buschchan save his first chance and his next chance go inches wide as Ukraine held on for a crucial victory.
Man of the match: Andriy Yarmolenko
He scored the opener and assisted on what turned out to be the eventual game-winner, showing his class. With him leading the Ukrainian attack, the Yellow and Blue could go a long way.
Ukraine have as much firepower as any team in the Euros
With Yarmolenko leading the way, ably assisted by Yaremchuk and Malinovsky, Shevchenko has a ton of options and the four goals they've scored plus all of the chances they've created over the first two matches bear that out. If they stay solid defensively, the rest of the field better watch out.
North Macedonia have played well so far, but have nothing to show for it
On their international tournament debut, the Lions have done far better than people expected, despite not picking up a point so far. Pandev and Alioski are class, but the rest of the side lacks composure in the key moments. Despite that, the experience is invaluable for the team and we will see much more of them as the years go on.