Portugal players after an automatic qualification in a dramatic defeat by Serbia (AFP)
The Azzurri and Cristiano Ronaldo's Portugal both finished second in their qualifying groups, behind Switzerland and Serbia respectively.
Italy will host North Macedonia in the play-off first round in March, with Turkey visiting Portugal, before the winners face off for a spot at next year's finals in Qatar.
The draw means that one of the last two European Championship winners will not be at the next World Cup. Portugal won the Euro 2016 title.
The winners of Portugal's match with Turkey will host the final-round game in Path C.
"It's a very difficult draw for us," said Italy coach Roberto Mancini. "North Macedonia is a very good team, and if we win we have to play away."
Italy -- who beat England on penalties in the Euro 2020 final earlier this year -- are hoping to banish the memories of their play-off heartache from four years ago when they lost to Sweden and failed to qualify for the World Cup for the first time since 1958.
Portugal have featured at every major championship since missing out on the 1998 World Cup.
They only narrowly missed out on automatic qualification when Aleksandar Mitrovic's late goal snatched a 2-1 win for Serbia in the two teams' last group match.
Elsewhere in the playoffs, British rivals Wales and Scotland could play each other in the final of Path A.
Scotland will welcome Ukraine to Glasgow in their semi-final game. Wales take on Austria in Cardiff, with the winners to have home advantage in the final.
The Welsh are hoping to play in the global showpiece for the first time in 64 years, while Scotland have not qualified since 1998.
"We've given ourselves a great opportunity," said Wales manager Robert Page.
"It was in 1958 that we last qualified for the World Cup finals and through the play-offs again, so the incentive is there for us.
"We worked ever so hard to get that runners-up position in the group and earn that home draw, and we've had the luck of the draw that if we win that semi-final we will also be home for the final, so there's everything to play for."
Russia face Poland in the Path B semi-finals, with the winners to host Sweden or the Czech Republic.
The Russians, who reached the 2018 quarter-finals as the host nation, have only ever lost one World Cup qualifier at home -- against Germany in 2009.
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