Alan Pardew's side, who were without their Senegalese star striker, conceded three goals in the first half, with Shola Ameobi coming off the bench to score a late consolation
Alan Pardew's men travelled to Portugal without star striker Papiss Cisse, who was left behind amid a disagreement with the club over his refusal to wear kit sponsored by loan company Wonga.
And Newcastle's lack of firepower proved telling as Rio Ave seized the initiative to seal a comfortable win.
Pardew plumped for a mix of youth and experience in his starting XI, with inexperienced goalkeeper Jak Alnwick and full-back Paul Dummett named alongside the likes of Yohan Cabaye, Steven Taylor and Jonas Gutierrez.
The St James' Park outfit started slowly, and quickly found themselves two goals behind, with Egyptian striker Ahmed Hassan netting a quick-fire double in the first nine minutes.
Newcastle's worries only increased, and after 26 minutes they were 3-0 behind as midfielder Braga scrambled home from close range.
The visitors did improve somewhat as the half wore on, and will have felt unlucky not to have cut the deficit as a Cabaye effort rattled the crossbar four minutes before the break shortly after Ederson had produced a fine diving save to deny Sylvain Marveaux.
Pardew made five changes during the interval, with Moussa Sissoko, Gabriel Obertan and Cheick Tiote all introduced into the action.
The alterations had an impact, with Yoan Gouffran shooting wide after good work down the right from Obertan after 57 minutes.
It was Gouffran's eventual replacement that would haul Newcastle back into the game however, as Shola Ameobi steered in Obertan's right-wing cross to reduce the arrears with 14 minutes to play.
The game ended sourly for the striker, though, as he was taken to hospital afterwards for x-rays on an arm injury, which forced him off.
Newcastle could not complete the comeback, though, and it was the hosts who wasted a chance to have the final say, substitute Sandro Lima seeing his penalty saved by Rob Elliot four minutes from the end after he had been bundled over by Mike Williamson.