Elimination at the last-16 stage could also mark the end of Ronaldo's international career, given that he will be 35 by the next European Championships and 37 by the next World Cup.
A stunning double from Edinson Cavani ensured that Uruguay saw off Portugal in a closely-fought match in Sochi.
Portugal have only once gone past the round of 16 stage at the World Cup since 1966.
And now they will likely have to find a new inspiration to take them further if Ronaldo is indeed going to step away from international football.
Ronaldo's long-term rival for individual honours, Lionel Messi, also crashed out of the competition earlier in the day.
Argentina were beaten 4-3 by France in a match littered with moments of magic and madness in Kazan.
France now go on to face Uruguay for a spot in the semi-final of the competition. SHARE THIS STORY USING ANY OF THE BUTTON BELOW ⬇ PLACE YOUR TEXT ADVERT BELOW ⬇⬇⬇