Timmy Abraham’s fourth-minute goal has given Newport County a 1-0 half-time lead over the Blues at Portman Road.
Centre-half Luke Woolfenden was the only survivor from the XI which started the 2-2 with Morecambe on Saturday.
Tomas Holy was in goal with Janoi Donacien, a sub against the Shrimps, skippering at right-back with Woolfenden and Corrie Ndaba the centre-halves.
Bailey Clements was handed his second senior start, his first having come in the same competition two years ago, at left-back.
In central midfield, neither Lee Evans nor Rekeem Harper was involved and Idris El Mizouni started alongside Cameron Humphreys with the 17-year-old handed his senior debut.
Armando Dobra was on the right, and Sone Aluko, also making his debut, were in the wide roles with Louie Barry, another debutant, behind Saturday’s last-gasp goal hero Macauley Bonne, who was making his full debut for his hometown club.
Kayden Jackson and youngsters Matt Ward, Fraser Alexander and Albie Armin were among the subs.
Newport boss Michael Flynn named an entirely changed XI from the one which beat Oldham 1-0 away in their opening fixture at the weekend including seven youth products. Ex-Blues midfielder Ed Upson was on the bench.
Prior to kick-off both teams and staff took a knee in protest against racism and inequality to applause from the Portman Road crowd.
Town went close to going in front in the third minute when Dobra brought the ball forward from a central area and hit a low shot across Exiles keeper Nick Townsend but off the outside of the post.
However, a minute later, the visitors went in front. Finn Azaz beat Aluko on the right of the area following a free-kick and crossed low for the unmarked Abraham, the younger brother of England international Tammy, to deftly flick past Holy.
Town quickly looked to get back on terms and in the seventh minute a cross from the right fell to Dobra, who hit a well-struck shot which Townsend batted away. The ball reached Donacien and the St Lucia-born full-back sent it back in for Bonne, who headed into the ground and over.
Newport threatened a second in the 12th minute when Jordan Greenidge turned the ball wide to Kevin Ellison, then burst into the area and only a timely intervention from Woolfenden prevented the Exiles forward from having a free shot at Holy from inside the area.
Chances were coming at both ends in an open early phase of the game. On 14 Barry broke into the area on the right and teed-up Aluko to his left but the Nigerian international, who was making an off-the-pace start to the match, air-kicked.
The ball eventually reached Clements breaking forward from left-back but his shot flew wide with Bonne trying to divert it goalwards with his head.
In the 18th minute Azaz belted a 25-yard free-kick deep into the lower tier of the Sir Bobby Robson Stand.
Two minutes later, Humphreys cleverly beat his man a third of the way inside the Newport half, then threaded an incisive pass through to the breaking Clements to his left. The academy product sent in a low ball but awkwardly for Bonne and keeper Townsend was able to claim.
On 21 Aluko was booked for a foul on Christopher Missilou, then Barry and Dobra combined well on halfway and the Albanian U21 international burst away towards goal but shot against a defender when returning the ball to the on-loan Aston Villa man might have been a better option.
Town were well in control and looking threatening going forward but with their approach breaking down with the final pass or decision. On 24 Humphreys found Barry at the far post with a lofted ball but the linesman’s flag had been raised.
Just after the half hour, an Aluko corner from the right eventually fell for Bonne at a tight angle and the Ipswich-born striker smashed a shot off the outside of the post.
Newport started to see more of the ball and space in the Town half when breaking. On 34 Holy grabbed Abraham’s low cross ahead of Greenidge.
Five minutes later, Aluko, who was finding his way into the game, feinted his way into the area and fed Donacien to his right. The right-back crossed for Bonne, who headed wide.
On 41 Aneurin Livermore was booked for a foul on Dobra just to the left of the penalty box. El Mizouni took the free-kick and hit a low effort at Townsend’s post which the keeper did well to get down to and push wide.
In the penultimate scheduled minute Donacien, who had had a good half, slipped Barry in on the right of the area and the Villa youngster shot into the side-netting at a tight angle.
Town continued to create opportunities in injury time with Bonne rising high to nod to Townsend’s right from Donacien’s right-wing cross but without enough power to concern the keeper.
The half ended with the visitors still in the lead although with the Blues having had plenty of chances.
Despite having gone behind for the second game in a row, Town quickly got control of the game and had had more than enough opportunities to be on terms having hit the woodwork twice, but will feel they should have been sharper with their finishing.
At the other end, Newport had served warning that a second goal was far from an impossibility on a number of occasions with Abraham and Greenidge both having caused problems.
However, if the game continues in the same vein in the second half, it seems likely the Blues will find their way back into the match sooner rather than later. If level at 90 minutes, the game will go straight to penalties.
The draw for the second round, which again is regionalised, is set to take place on Wednesday evening live on Sky Sports following the Leyton-Orient-QPR tie. The draw is also live on Twitter via @Carabao_Cup.
Town: Holy, Donacien (c), Woolfenden, Ndaba, Clements, El Mizouni, Humphreys, Dobra, Barry, Aluko, Bonne. Subs: Hladky, Armin, Alexander, Fraser, Ward, Jackson, Norwood.
Newport: Townsend, Clarke (c), Lewis, Hall, Abraham, Azaz, Ellison, Missilou, Greenidge, Woodiwiss, Livermore. Subs: Ovendale, Upson, Telford, Collins, Hillier, Lewis, Karadogan. Referee: Neil Hair (Cambridgeshire).