The Pilgrims play host to a side which has gone eight games unbeaten in the fourth tier, after winning just one of their last six outings themselves.
Match preview
Ceding top spot to new League One leaders Ipswich Town, a grim goalless draw at Cambridge United on Saturday saw Plymouth's troubled spell continue, following what had been a fantastic start to the season.
Though victory would have seen them retain first place in the table, Steven Schumacher's side managed just one shot on target - and also hit the crossbar - to record a third draw from their last four league matches.
The other fixture during that spell was last week's 2-0 home defeat to Port Vale, which ended the Pilgrims' proud 100% home record, and they now sit a point behind Ipswich and two clear of third-placed Sheffield Wednesday.
Schumacher, still only 38, has already claimed back-to-back EFL Manager of the Month awards this season, and last month signed a new contract to keep him at Home Park until 2027.
Now experiencing his most prolonged downturn, his side only missed out on the League One playoffs on the final day of last season - in addition to suffering an extra-time FA Cup loss to Chelsea - and, more recently, were dumped out of the cup in less glorious fashion via a 5-1 drubbing by Grimsby.
He will surely remain confident of turning things around, though, and the next opportunity to do so comes in midweek, when Plymouth return to a competition in which they topped their group ahead of Bristol Rovers, Swindon Town and Crystal Palace's Under-21s, before going on to beat Charlton 3-2 in the first knockout round.
Wimbledon, meanwhile, tackle Tuesday's third round tie having pipped Portsmouth, Crawley Town and Aston Villa's young guns to first place in their group. They then edged out Sutton United 1-0 in the second round.
Like Plymouth, the South London side were held to a 0-0 draw at the weekend, with their stalemate at Swindon denying them a third league win on the spin.
Nonetheless, Wimbledon have started the month with four points from a possible six, after manager Johnnie Jackson was awarded the EFL League Two Manager of the Month award for November. The former Charlton boss picked up that accolade having steered his squad to a total of seven points from three fixtures against fellow promotion hopefuls.
Now only three adrift of the playoff places, amid a packed mid-section of the table, Jackson's side have not had things all their own way over recent weeks, as they were eliminated from the FA Cup by means of a 2-0 second round defeat to National League high-flyers Chesterfield.
As they undertake the journey south to Devon, then, they will hope a defence which has kept six clean sheets in their last eight matches can hold out against League One opponents and see them through to the fourth round.
Plymouth Argyle EFL Trophy form:
W
W
W
W
Plymouth Argyle form (all competitions):
L
D
D
W
L
D
AFC Wimbledon EFL Trophy form:
W
W
L
W
AFC Wimbledon form (all competitions):
W
W
W
L
W
D
Team News
With another important league fixture to come on Saturday afternoon, Steven Schumacher could make several changes to his Plymouth side - particularly as they have also failed to score in their last two games.
Mickel Miller made his first league start for Argyle at the weekend and may be retained on the left wing, but Niall Ennis, Bali Mumba and Nigel Lonwijk are among those who were dropped against Cambridge and could now return.
The chance for defender Dan Scarr to play more minutes also arises, after the ex-Walsall centre-back finally returned to action following more than a month on the sidelines. Despite drawing a blank last time out, both Sam Cosgrove and top scorer Ryan Hardie will hope for another opportunity up front.
Meanwhile, Wimbledon are expected to select young Nathan Broome in goal; replacing first-choice Nik Tzanev, who has played every minute of the league campaign so far - with eight clean sheets under his belt.
Wales stalwart Chris Gunter is back in contention following his trip to Qatar for the World Cup and could bring some valuable experience to the visitors' defensive line.
As in the previous round, forwards Ethan Chislett, Ayoub Assal and Josh Davison may be rested, but would play a part from the bench if required.
Plymouth Argyle possible starting lineup:
Burton; Lonwijk, Wilson, Galloway; Mumba, Jenkins-Davies, Randell, Miller; Roberts, Ennis; Cosgrove
AFC Wimbledon possible starting lineup:
Broome; Biler, Jenkins, Pearce, Currie; Bendle, Woodyard; Senior, Pell, Fisher; Hudlin
We say: Plymouth Argyle 1-0 AFC Wimbledon
At this stage of the competition, if the scores are level at the end of 90 minutes the winner is then decided by penalties - but Plymouth can end their barren spell by breaching a watertight Wimbledon defence.