Four second half goals see County fall to defeat at Home Park.
The Exiles made the allocated six changes for the fixture, with Jack Compton, Tom Owen-Evans, Ben Tozer, Jordan Green, Jazzi Barnum-Bobb and debutant Liam Angel, all making up the starting XI for the Checkatrade Trophy fixture.
The home side made seven changes to the side that played against Blackpool on Saturday, with loanee Craig Tanner named in the starting XI, with right-winger having history against County in cup competitions, having scored for Reading against the Exiles in August 2014 in our League Cup encounter.
County had the first chance of the game in the opening minutes when a deep corner fell to Jon Parkin at the far post. The striker was patient and waited for the ball to drop, before hitting a powerful effort on goal that was deflected clear.
The deadlock was broken in the 19th minute when a menacing run down the left by Myrie-Williams allowed the winger to direct a powerful cross into the area that was met at the far-post by the advancing Jordan Green, who kept his composure well to send a driven effort past Vincent Dorel.
Just before the half-hour mark Joe Day was forced into action to push away a powerful effort by Jordan Slew, which on target from just inside the County area.
Slew was again involved for the host just prior to the break when the forward found space to launch a shot on target that took a heavy deflection by Ben Tozer that saw the ball flash wide of the left-hand post.
Into the second half and the Exiles looked to continue their energetic outlook on the game, with Tom Owen-Evans breaking from deep and the midfielder was able to pick out a pass to Jon Parkin. The striker cut inside the area and was able to manufacture some room to get a shot away, but his effort was blocked shortly after leaving his boot.
Plymouth was back level within six minutes after the restart when a cross from the right was met by Jordan Slew, who empathically headed home from close range.
Just minutes later the home side were in front when Jake Jervis was able to latch onto a diagonal pass into the area, and the forward was able to lift his finish neatly over the advancing Joe Day to put Plymouth ahead.
The hosts were able to add a third when a free-kick on the perimeter of the County area was flicked to the far post, where centre-back Nauris Bulvits was waiting to head home.
County used all three substitutes but were unable to carve our any real opportunities during the final forty-five minutes, as Plymouth enjoyed the majority of possession at Home Park.
Inside the final ten minutes, Plymouth had a chance to extend their lead further when a powerfully struck volley by David Fox was held well by Joe Day on the ground after the 'keeper had to dive down to his right.
In stoppage time Plymouth added a fourth when a chipped cross from the right was met by Craig Tanner, who calmly side-footed the ball into the back of the net.
FINAL SCORE: PLYMOUTH ARGYLE 4 - 1 NEWPORT COUNTY AFC
STARTING XI: Day, Bignot, Angel, Barnum-Bobb, Bennett (c) (Butler), Tozer, Myrie-Williams, Compton (Rigg) , Green, Owen-Evans, Parkin (Jackson)
SUBS: Bittner, Butler, D.Jones, Daf.Jones, Labadie, Jackson, Rigg
BOOKINGS: Bignot
GOALS: Jordan Green
REFEREE: Andy Davies
Attendance: 2,349