The League One hosts are set to play their first-ever game in the quarter-finals of the competition, while Boro are appearing at this stage for the first time since the 2018-19 season.
Match preview
Port Vale are enjoying the best EFL Cup run of their 147-year history after successfully negotiating four rounds of matches, beginning with a narrow 3-2 win over fellow League One side Fleetwood Town in August.
They subsequently held their nerve from the penalty spot to claim a shootout win against Crewe Alexandra, before edging out Sutton United via a 2-1 scoreline to set up a third-round clash with Mansfield Town.
Tottenham Hotspur Alfie Devine proved to be the hero in last month's tie when he found the net in the 50th minute to write his name in Port Vale history and secure the club a place in the last eight.
Although the Valiants may have been dreaming of a tie against the likes of Chelsea or Liverpool, they could Tuesday's meeting with Championship opposition as a realistic chance to spring a surprise and sneak into the final four.
They will head into their big cup outing in a positive mood after they claimed a 3-2 victory over Wigan Athletic in a game where the Valiants gave up a two-goal lead, before Ethan Chislett netted a late winner to complete his hat-trick and secured all three points to leave his side in 15th position.
The result also represented their first home win in regulation time since September, giving them a timely confidence boost ahead of Middlesbrough's visit to Vale Park.
Middlesbrough are competing at the quarter-final stage after winning four away matches, including a narrow victory over fellow Championship side Huddersfield Town to get their cup journey up and running.
They went on to beat League One outfit Bolton Wanderers 3-1 and fourth-tier Bradford City 2-0 to continue their run in the competition.
In their most recent cup outing, goals from Morgan Rogers, Samuel Silvera and Emmanuel Latte Lath guided Boro to a 3-2 victory over third-tier Exeter City, sealing their place in the last eight where they have been given yet another away tie.
While Michael Carrick's side have enjoyed success in the EFL Cup, they have struggled for consistency in the league, having won nine, drawn three and lost 10 of their 22 Championship matches.
Three of those defeats took place ahead of Saturday's trip to Wales, where Middlesbrough beat Swansea 2-1 to return to winning ways thanks to a Sam Greenwood effort and a Silvera strike.
After scoring at least two goals in nine successive away games, Boro will be confident they have the firepower required to get the better of Port Vale and reach the EFL Cup semi-finals for the first time since winning the competition in 2003-04.
Port Vale EFL Cup form:
W
W
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Port Vale form (all competitions):
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D
L
W
L
W
Middlesbrough EFL Cup form:
W
W
W
W
Middlesbrough form (all competitions):
L
W
L
L
L
W
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Team News
Andy Crosby's side are still unable to call upon the injured trio of Mitchell Clark, Dan Jones and Josh Thomas.
James Wilson, who has been sidelined since October 10, appears to be closing in on a return to fitness, but Tuesday's contest may come too soon for the striker.
After dropping down to the bench at the weekend, Nathan Smith could come back into the side to feature in a back three with Jason Lowe and Jesse Debrah.
As for Boro, their injury list features Paddy McNair, Tommy Smith, Darragh Lenihan, Hayden Hackney, Lewis O'Brien and Marcus Forss.
Midfielder Riley McGree is nearing a return to training following a spell on the sidelines with a foot injury, but the Australian remains unavailable for Tuesday's cup tie.
Having featured in the previous four cup games, goalkeeper Tom Glover is set to come back into the team, especially after first-choice shot-stopper Seny Dieng was forced off in the closing stages of Saturday's win over Swansea.
Port Vale possible starting lineup:
Ripley; Smith, Lowe, Debrah; Massey, Arblaster, Ojo, Grant, Chislett, Devine; Garrity
Middlesbrough possible starting lineup:
Glover; Dijksteel, Fry, Van den Berg, Bangura; Howson, Barlaser; Jones, Crooks, Greenwood; Latte Lath