After beating Egypt 2-1 last week, Portual lost to an inspired Dutch side 3-0 in Geneva thanks to goals from Memphis Depay, Ryan Babel and Virgil van Dijk.
Depay struck early with his 11th minute opener before former Liverpool forward Babel doubled their lead shortly after the half-hour mark.
Newly named Dutch captain Van Dijk wrapped up the win by adding a third just before the break.
The game ended Ronaldo’s run of scoring in nine consective games, but the Real Madrid forward remained a hit with the fans.
A number of supporters invaded the pitch shortly after the hour mark and one fan decided to try and kiss Ronaldo and tried to get a snap with the Portugal skipper.
Another fan wearing a Real Madrid shirt also ran onto the field and hugged Ronaldo before being hauled off the pitch by security.
Ronaldo was later replaced by Joao Moutinho 22 minutes from time.
Portugal coach Fernando Santos took responsibilty for the defeat.
“It could have gone better but the responsibility for the defeat is mine. I was the one who picked the team, watched our opponents and put together our strategy,” he said.
“We don’t like to draw matches, let alone lose them. I will draw my conclusions. We need to find something positive in this defeat.”