With an hour gone at Windsor Park on Friday night, O'Neill would have been contemplating a famous World Cup qualifying victory with his side 2-1 up and Portugal having lost Helder Postiga to a red card.
But Chris Brunt and Kyle Lafferty were both dismissed to allow Paulo Bento's side back into the game and Real Madrid superstar Cristiano Ronaldo obliged with a 15-minute hat-trick to seal a 4-2 win.
Brunt and Lafferty will now be absent when their team-mates fly to Luxembourg on Sunday morning and O'Neill has other problems to deal with too.
He confirmed that Derby forward Jamie Ward, who has excelled in his last two appearances and scored his first international goal against Portugal, is a doubt alongside Shane Ferguson.
Both were subsituted in the second half in some discomfort, while an Irish Football Association official said that Niall McGinn was also nursing an injury.
With Aaron Hughes, Ryan McGivern and Craig Cathcart already injured before the squad met in Belfast, O'Neill could potentially be down to the bare bones.
"We will have to sit down and assess our options," he admitted.
"As well as the red cards the biggest blow is a couple of injuries.
"Wardy is possibly out and Fergie may not be available, so that will give us something to think about."
O'Neill has limited options outside of the squad and appears unlikely to delve into a very inexperienced under-21 pool.
"You have to look at the players that would be available," he said.
"Stephen Robinson has the under-21 lads in Belgium now and it would be a bit unfair to call on his players. Most of his lads have no first team football experience...it's a big ask."
Paddy McCourt is an obvious solution to bolster the numbers.
The winger was not originally selected after a disrupted pre-season left him short of match fitness, but he is now in full training with new club Barnsley.
Reduced numbers meant O'Neill was already forced into brave team selection against Portugal.
He pitched 21-year-old MK Dons defender Lee Hodson against Ronaldo at right-back, while attacking midfielder Brunt was deployed as an emergency left-back.
Both selections raised eyebrows, but O'Neill believes he had no real choice.
"They are only gambles if you have got other options," he said.
"It wasn't really a gamble, it was a no-brainer.
"I had one available right-back in Hodson and my gamble was that I played him at right-back.
"I though Lee was magnificent, coming in in those circumstances.
"The decision with Chris came because I didn't want to take energy out of the front six. I could have played him and Shane in either position on the left but Brunty has not played any first-team football for West Brom this season and by his own admission felt he'd be better suited to left-back.
"Those decisions had to be made."