Miguel Almiron is injured and will be out for three weeks, according to Paraguay coach Guillermo Barros Schelotto.
Almiron is Newcastle United's leading scorer, having netted 11 times in the best season of his Premier League career.
His goals – six of which came in October as he was named the Premier League Player of the Month – have fired Newcastle into top-four contention.
Although Almiron's form has been less impressive in 2023, seeing him dropped last week, he scored a much-needed winner as a substitute against Wolves.
But Newcastle are now set to be without the winger, with Schelotto explaining he had suffered an unspecified setback in Magpies training that would also rule him out of international action.
"Miguel Almiron was injured yesterday and will be out for three weeks," Schelotto told reporters in Paraguay on Friday.
"It is not necessary for him to come [on international duty].
"We received the report from his club, and we saw the video of the injury."
Newcastle, who are already without £45million January signing Anthony Gordon, face Nottingham Forest on Friday before a huge game against Manchester United at the start of next month.
Jacob Murphy was preferred to Almiron against Wolves and is likely to deputise, although he has only two goal involvements in 25 matches this term.
Almiron, who also has a single assist, has scored 30 per cent of Newcastle's Premier League goals in 2022-23 – the highest share by a Magpies player in a single campaign since Loic Remy in 2013-14 (33 per cent).
Newcastle enter the weekend fifth in the table, four points behind fourth-placed Tottenham with two games in hand.
