The Belgian club are six points clear of their Portuguese counterparts in the league table and on course for direct entry to the knockout rounds; meanwhile, Porto are just inside the playoff places.
Match preview
Though they narrowly failed to keep their 100% record intact last time out, Anderlecht are one of four teams tucked behind flawless leaders Lazio at the midpoint of the new league phase.
Les Mauve et Blanc went 1-0 up in the 85th minute before drawing with Latvia's RFS earlier this month, becoming only the sixth team to score the opening goal so late in a Europa League match without going on to win.
Nonetheless, they have otherwise flourished since the departure of former boss Brian Riemer, and 36-year-old coach David Hubert has made quite an impact, getting the best out of underperforming stars such as Kasper Dolberg, who has scored five goals in his last two league games.
Indeed, Anderlecht racked up 11 goals in two wins either side of the international break, swatting aside Cercle Brugge and then nine-man Gent to claim fourth spot in the Belgian Pro League standings.
Following victories over Ferencvaros, Real Sociedad and Ludogorets earlier this season, the 1983 UEFA Cup winners are also in a strong position to reach the Europa League's knockout rounds.
They can now take one step closer by winning their first meeting with Porto since qualifying for the 2000-01 Champions League, which ended in a 1-0 aggregate victory over two legs.
Including that tie 24 years ago, Porto have lost all four of their away games against Anderlecht to date, failing to score a single goal and conceding nine in the process.
That bodes ill for a side struggling to meet expectations both in Europe and on the domestic scene, as the Dragons have recently lost three straight games amid turmoil off the pitch.
Leaving the Portuguese giants on their worst run since 2008, Sunday's shock 2-1 defeat against third division Moreirense in the Taca de Portugal was followed by angry ultras attacking the club bus with projectiles including fireworks.
After losing to Lazio, then 4-1 to old foes Benfica, tensions were already high, but many fans are now demanding the resignation of coach Vitor Bruno, who took over from the highly successful Sergio Conceicao in the summer.
Chairman Andre Villas-Boas may make a decision on his manager's future soon, though Porto are still second in the Primeira Liga, six points behind Sporting, who have just lost their coaching staff to Manchester United.
Sitting 22nd in the Europa League, a morale-boosting midweek win would be welcome; but they have managed just one from their last 14 away matches in the competition, keeping no clean sheets and conceding 33 goals along the way.
Anderlecht Europa League form:
W
W
W
W
W
D
Anderlecht form (all competitions):
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L
W
D
W
W
Porto Europa League form:
L
D
W
L
Porto form (all competitions):
W
W
W
L
L
L
Team News
While Anderlecht are anticipating the imminent return of experienced stars Jan Vertonghen and Thorgan Hazard, on-loan midfielder Leander Dendoncker is back at David Hubert's disposal this week.
Before the international break, the Aston Villa loanee suffered an ankle injury that ruled him out of four matches, but he appeared as a substitute on Sunday.
Once again, in-form Kasper Dolberg is set to start up front, aiming to boost his meagre European goal record of just one in 10 games to date.
Meanwhile, Porto could make several changes following their recent slump - and after some unsuccessful rotation in the Portuguese cup.
Two key attackers should return, as Galeno set up the Dragons' goal against Lazio and has also created the most chances (six) and made the most dribbles (14) of any Porto player in this season's Europa League; Spanish striker Samu Aghehowa has found the net four times in the league phase so far.
Fran Navarro, Otavio, Wendell and Serbian midfielder Marko Grujic all feature on a long list of absentees due to injury.
Anderlecht possible starting lineup:
Coosemans; Sardella, Simic, Jorgensen, N'Diaye; Verschaeren, Rits; Dreyer, Stroeykens, Edozie; Dolberg
Porto possible starting lineup:
Costa; Fernandes, Perez, Djalo, Moura; Varela, Estaquio; Vieira, Nico, Galeno; Samu
We say: Anderlecht 2-2 Porto
While the two teams are in contrasting form, Porto still pack a punch and can perhaps steal away from Lotto Park with a point.