Ivan Sanchez got the scoring underway with a wonderful virtuoso effort with what was the first of four goals before the break.
Mitch Pinnock and Nicke Kabamba turned the game on its head for Northampton before Lukas Jutkiewicz's trademark header saw the teams go in level.
The Cobblers took the spoils virtue of a deflected Caleb Chukwuemeka strike that came midway through the second period and amidst unrelenting pressure from the visitors.
Earlier in the day, Blues beat a Salford City XI at Wast Hills Training Ground.
Lee Bowyer named a strong starting XI for Blues' fourth pre-season outing and second of the day. Matija Sarkic was named between the sticks as he continues his trial period in front of the same defensive unit that begun the game at the Jonny-Rocks Stadium last weekend. Gary Gardner, who signed a contract extension earlier in the week, and summer recruit Ryan Woods were again partnered in the middle of the park.
As with a week ago at Cheltenham Town, Blues made a lightning-quick start on the road and opened the scoring with just five minutes on the clock thanks to Sanchez.
Blues fans were unable to be in attendance for the Spanish wizard's goal of the season at Cardiff City last term but were left drooling in the away end over his latest effort. A trademark, jinking solo run was capped off with an emphatic finish to chalk up an early lead.
However, the hosts restored parity almost as swiftly as they had lost it when they equalised through Pinnock in the 12th minute. The summer arrival from Kilmarnock made no mistake as he swept home from inside the penalty area after Benny Ashley-Seal had funnelled the ball through a line of yellow-clad visiting defenders.
Blues, roared on by an impressive travelling contingent, responded with a continuation of their passing football approach and created a chance for Jutkiewicz who was able to force a save out of Jonny Maxted.
The Club's top-scorer last term was ably supported by the energy and selfless running of Jonathan Leko, with it seeming Blues were soon to regain their advantage. Although, against the run of play, it was Northampton who found the net for a second time when the typically accomplished footwork of Matija Sarkic momentarily deserted him to allow Kabamba the simplest of close-range finishes.
But if that was uncharacteristic, then the manner of Blues' leveller was anything but. As soon as Kristian Pedersen lined up a cross from the left flank, eyes and then the ball drifted into the middle where Jutkiewicz was making his move. The frontman acted ruthlessly between the standstill home defenders to head in comprehensively and put Blues back on level terms after 38 minutes.
Half-time: Northampton Town 2-2 Blues
There was clear intent from Blues at the beginning of the second-half and it seemed certain that in what had been a topsy-turvy encounter until then that they would be the next to strike. For the quarter of an hour that followed the interval, Northampton were camped inside their own penalty area as they required everyone in a brave defensive effort.
All of Sanchez, Gardner and Woods set their sights with powerful attempts and the onslaught forced the hand of Jon Brady to make a series of changes in an attempt to disrupt Blues' flow. Yet the pressure continued and particular joy was being found down either side, with Jutkiewicz licking his lips at the prospect of further aerial deliveries.
You sensed it would take a breakaway for anyone other than Bowyer's side to be victorious and so it proved in agonising fashion. Just moments after coming on, Chukwuemeka appeared to be buying his teammates a breather but instead embarked on a mazy run forward that resulted in a deflected effort creeping into the Blues goal after 68 minutes.
This goal only served to increase the flow of one-way traffic and Gardner went close with a header on the stretch as the screw continued to be turned. But when the crossbar was hit twice from consecutive headers as Northampton hung on for dear life, it ultimately signalled that victory was not to be Blues' on an afternoon when more minutes into the legs and the return of Bluenoses took on the greater significance.
After an absence of 16 long months, having the loyal Blues support backing the team at Sixfields was always going to be the defining memory of this match.
Blues lost for the first time this pre-season but will not lose focus that what really matters is the scoreline at Bramall Lane in two weeks time.
Northampton Town (4-4-2): Jonny Maxted (Liam Roberts 67), Aaron McGowan (Sid Nelson 65), Ali Koiki (Joseph Mills 56), Fraser Horsfall, Jon Guthrie, Paul Lewis (Scott Pollock 74), Jordan Flores, Dylan Connolly (Caleb Chukwuemeka 56), Mitch Pinnock, Nicke Kabamba (Michael Harriman 56), Benny Ashley-Seal (Liam Cross 76).
Substitutes not used: Josh Flanagan, Max Dyche.
Blues (4-4-2): Matija Sarkic, Maxime Colin, Harlee Dean (captain), George Friend, Kristian Pedersen, Ivan Sanchez (Remi Walker 74), Ryan Woods, Gary Gardner, Jeremie Bela, Jonathan Leko, Lukas Jutkiewicz.
Substitutes not used: Connal Trueman, Rico Browne, Caolan Boyd-Munce, Keyendrah Simmonds, Kyle Hurst.
Referee: Andy Woolmer
West Bromwich Albion are the visitors to St. Andrew's next weekend as Blues play their fifth and final pre-season game ahead of a Sky Bet Championship opener against Sheffield United in early August. Tickets for the Baggies clash are on sale now.