The Real Madrid forward had already netted two first-half goals to put his side ahead, only for Diego Costa to score either side and Nacho - at fault for the Selecao's opener - to complete the stunning turnaround.
After De Gea's blunder caused pity and scorn around the world and later a hug from Hierro, a former Spain mainstay as a player, and after they all went to half-time, Spain's offence really got pretty, even off a free kick.
"'We'll be back soon for Spain v Ronaldo' quite a disrespectful statement to make against the current European champions", Twitter user @wallace92hfc wrote. It will be only their second ever meeting in a World Cup after Spain beat Portugal 1-0 in the quarter-final on their way to the title at the 2010 showpiece in South Africa.
Meanwhile, Spain playmaker Isco echoed Hierro's praise of the team's resiliency, adding they can take nothing for granted this summer.
One of the most promising young talents in the tournament, Portugal's 21-year old rising star Goncalo Guedes will definitely be worth keeping an eye out for, when they start things off against Spain in Sochi.
Heading in to the 2018 World Cup, the most anticipated matchup was the Group B showdown between powerhouses Spain and Portugal.
He redirected it back the other way and off the left post, then it pinballed over way right until it came to rest with the score 3-2.
Friday's earlier games were both settled by late winners but Ronaldo was immediately in the thick of the action, tumbling under a rash challenge from Nacho, who was deputising for Dani Carvajal, another Real Madrid team-mate. "This was only the first match but we are going to believe until the end". Ronaldo did not feature in any of Portugal's pre-tournament friendlies, but will no doubt, be a part of Fernando Santos' starting line-up on Friday.
Spain, trying to rebound from disappointing eliminations at the 2014 World Cup and the 2016 European Championship, will next face Iran, while Portugal plays Morocco.
A game that looked lively from the off, Ronaldo engineered Portugal's opening; forcing his club-mate Nacho into a clumsy foul that allowed Ronaldo give his side the lead from a resulting penalty. I am happy with the way the team reacted, we deserved more but football is like that, this can happen to you.
His second goal came after a blunder by SpaingoalkeeperDavid de Gea, who let the ball bounce off his hands and into the net.
Busquets and Costa combined for Spain's equalizer in the 55th.