Reece Marshall scored twice but the Wanderers' fightback fell short as Newcastle Falcons won 41-15 at Kingston Park on Monday night.
Marshall's double, which added to the try on his comeback against London Irish last week, and an effort from guest player Jack Spittle gave the Saints second string hope.
But Newcastle, who had been 17-0 and 20-5 up, had the final say as Mickey Young, Kyle Cooper and Nemani Nagusa scored in the final 10 minutes to make sure of the win in the Premiership Rugby Shield match.
It was the first defeat of the season in competitive action for the Wanderers, who had also lost in a friendly against London Irish seven days earlier.
But they did not go down without a fight as they overcame a sluggish start to reduce the deficit to just five points at one point during the second period.
Newcastle had two men sin-binned to the Wanderers' one, but the away side were left to rue the lack of a full-time kicker as full-back Tom Emery missed all three of his conversions.
The Falcons had got the scoring started when they drove over, with Connor Collett collecting the try.
Fly-half Brett Connon added the extras with aplomb to give his team an early 7-0 advantage, and it was 14-0 soon after as Connon converted Tom Arscott's try.
The Wanderers had been making costly early errors and the concession of another penalty gave Connon a further three points as the gap between the teams continued to increase.
Newcastle were bossing the breakdown with the Wanderers struggling to support their carriers, but they did finally manage to apply some pressure after winning a scrum penalty.
The away side were held up under the posts and they then lost Jamal Ford-Robinson to what appeared to be a knee injury following a scrum.
Newcastle stood tall in defence, pushing the Wanderers back and eventually forcing a knock-on.
But after Tom Wood did well to win a penalty at the breakdown, pressure was applied in the lineout and Falcons lock Will Montgomery was sent to the sin bin.
The Wanderers made their opponents pay immediately, with another lineout drive resulting in a try for hooker Marshall.
But Senior Academy player Emery was unable to make the conversion.
The tide was really turning, with the Falcons getting on the wrong side of the referee.
And the Wanderers scored again early in the second half, with Nottingham wing and former NSB pupil Spittle showing good awareness to intercept a pass and race in for the score.
Emery again sent his conversion attempt wide, but the Wanderers were well on top in terms of possession.
And after a string of penalties were conceded by the Falcons, flanker Tom Marshall became the second player sin binned for the home side.
The Wanderers needed to make their abundance of possession count, but they were held up after forcing their way over the line.
Eventually the third try came though, with Marshall scoring his second from a lineout drive.
Emery missed his most simple conversion of the night as the Wanderers continued to rue the lack of a recognised fly-half.
The Falcons then finally got some possession, having been shorn of it for so long, and after a big scrum in front of the posts, scrum-half Young picked up to score.
Connon again converted to make it 27-15 and the Wanderers were then reduced to 14 men as replacement Morgan Dayes was punished for a high tackle on Josh Hodge.
Cooper took immediate advantage, scoring from a lineout drive, with Connon adding the extras.
Newcastle still had time to score again, with Nagusa going over and Connon converting to put the icing on the cake.
Newcastle Falcons: Arscott; Radwan, Stevenson, Bettencourt, Kibiridge; Connon, Stuart; Davison, Blamire, Mitchell; Montgomery, G Young; Marshall, Collett, Burrows (c).
Replacements: Cooper, Payne, Wilson, Nagusa, Graham, M Young, Wilson, Hodge.
Wanderers: Emery; Worley, Sleightholme, Strachan, Spittle; Furbank, Tupai; Davis, Marshall, Ford-Robinson; Moon, Onojaife; Wallace, Ryan, Wood (c).
Replacements: Ma'asi, Culverhouse, Garside, Coles, Povoas, Dayes, Whyte, Evans.