Newport manager Justin Edinburgh refused to blame his side's midweek Capital One Cup exertions - or the form of home goalkeeper Matt Duke - for County's first setback of the season.
Jacob Blyth marked his Northampton debut with the opening goal as the hosts won 3-1 at Sixfields.
Signed on loan from Leicester only 24 hours earlier, the young striker gave the Cobblers the early lead which Roy O'Donovan doubled in the first half.
Gary Deegan added a third goal late on before substitute Connor Washington grabbed a late consolation for Newport.
The Exiles marked their return to the Football League after a 25-year absence by beating Accrington 4-1 last weekend and followed it up with an impressive Capital One Cup win at Brighton on Tuesday night.
Edinburgh said: "The scoreline was very harsh on us and anyone here could see that we gave a good account of ourselves. We don't like to lose but we weren't ruthless enough in the box.
"Extra-time at Brighton didn't take that much out of us and the players didn't look jaded. Their keeper was man of the match but in all fairness we gave him the opportunity to make the saves.
"The performance was good and we put Northampton on the back foot for long periods. But we had a 10-minute spell in the first half when we lost our way a bit. There were chances here to get goals and we just haven't taken them.
"We started really well but if you don't take your chances you must make sure you don't give easy chances away. I'm disappointed with the goals we conceded but it's a learning curve for us.
"If we continue to play like that we'll pick up more points than we lose. I'm sure we're capable of competing in this division."
Northampton boss Aidy Boothroyd was relieved to see his side up and running.
The Cobblers boss is still without some of his key players so he was happy to see his side bounce back from last week's opening-day defeat a York and the midweek cup loss to MK Dons to pick up all three points.
"It is a relief considering our big players are out but it was a tough game and sometimes you need a game like that to make you realise what football is all about,'' said Boothroyd.
"You come back from your summer and you have to make sure you hit the ground running because teams like Newport will be at it, and they really were.
"For the first 15 minutes it was like the Alamo and we were just doing what we could to keep them out. They were very, very good.
"I do think that we gave them two or three opportunities through unforced errors that allowed them to get some momentum and get back into it. But in the end the result was deserved."