But the milestone day almost turned into a nightmare as Ramos squandered two penalties in the stalemate, after not having not missed in his previous 24 attempts for either Spain or Real Madrid.
The defender -- who captains both club and country -- has now played one international game more than the previous record holder, former Italy goalkeeper Gianluigi Buffon, who retired from international duty in 2018.
Ramos, 34, is now targeting the world record held by Egypt's Ahmed Hassan, who played 184 games for his country between 1995 and 2012. The defender could reach that mark at next summer's Euro 2020 tournament, if he features in all of Spain's matches before then.
But Spain coach Luis Enrique said Ramos's twin spot-kick misses would not affect his captain.
"Sergio's numbers when it comes to taking penalties are in the reach of few players. If we had got a third penalty or a fourth one he would have taken them as well," he said. "He had scored his last 25, but football has moments like this."
The number one spot-kick taker for Real Madrid and Spain, despite being a defender, Ramos has turned penalty taking into an art in the last two years, with his last miss coming when he hit the crossbar in Madrid's 3-2 defeat by Sevilla FC in May 2018.
He has confessed to relishing the high-stakes situation of a penalty, scoring a number of crucial spot-kicks in Real's run to the La Liga title last season as well as netting from the spot in last month's 3-1 win at Barcelona.
But he finally met his match in Swiss keeper Yann Sommer, who guessed the right way to parry Ramos' first penalty early in the second half and then refused to be fooled by the Spaniard's 'Panenka' routine which has worked so well for him in the past.
"It's a real shame that Ramos missed the penalties because he's usually so good," added Spain forward Dani Olmo.
"But he's very strong mentally and I'm sure that the next time he takes a penalty he'll score."
De Gea had started Spain's last four Nations League matches but made a costly mistake in a 1-0 shock loss to Ukraine in October. Luis Enrique came to defence of the embattled keeper following that defeat, saying it was a "bad habit" for critics to keep blaming him for his rocky form at club and country.
It was Simon's second straight start, as he was between the posts for Wednesday's friendly 1-1 draw against the Netherlands.
As for Ramos, Saturday's start further entrenches a remarkable international career that began when he made his Spain debut in March 2005, coming on for Carles Puyol at half time in a 3-0 friendly win over China.
He initially featured as a right back -- including at Euro 2008, Spain's first tournament win in 44 years, and in the country's only World Cup winning side in 2010 -- before switching to centre back for their defence of the European Championship title in 2012.
Despite turning 35 next March, he has expressed a desire to feature not just at the Euros in June, but also the Tokyo Olympics, describing the possibility as "a nice idea, an event no-one would say no to."