Marega, filling in for the injured Vincent Aboubakar up top, netted 22 goals in Primeira Liga last term, but doubled his tally for this season when he took advantage of abysmal marking to head home a corner from former Galatasaray man Alex Telles.
Things would have been different if not for Casillas, however, with Porto's goalkeeper pulling off two superb saves towards the end of the first half.
Casillas' clean sheet should have been ruined late on, but both Rodrigues and Sinan Gumus failed to convert good chances as Porto held firm to move top of the group.
Galatasaray started well and could have had the lead when Henry Onyekuru picked out Gumus, but Maxi Pereira was on hand to make a vital block.
Porto rallied, though, Jesus Corona teeing up Yacine Brahimi, whose acrobatic attempt was brilliantly kept out by Fernando Muslera.
Not to be outdone, Casillas was in equally fine form at the other end, Porto's goalkeeper denying both Yuto Nagatomo and Gumus in quick succession.
Marega made those saves count four minutes into the second half, easily getting the better of Galatasaray's static defence to nod in from Telles' delivery.
Rodrigues blazed over from close range and Gumus headed wide as Galatasaray searched for an equaliser, but it was Marega who should have had the final say with seven minutes remaining.
Muslera got down to deny Marega a second, though the miss ultimately mattered little as Porto got their first Champions League Group D win on the board.
What does it mean: Porto move top, Galatasaray's defensive woes continue
Galatasaray kept their first clean sheet in 19 European games on matchday one against Lokomotiv Moscow, but their leaky defence came back to haunt them once again on Wednesday, and Fatih Terim must find a way to shore up their backline.
Porto, meanwhile, are top of Group D with four points.
Casillas rolls back the years
Playing in his record 20th Champions League campaign, Casillas was crucial to Porto's victory, making two outstanding stops to keep Galatasaray out when they were on top in the first half.
Rodrigues, Gumus fluff their lines
Rodrigues was the hero on matchday one for Gala, but could not find the composure needed to salvage a share of the spoils when he was put through one-on-one with Casillas in the closing stages before Gumus - who spurned two golden opportunities in the first half - headed wide from point-blank range.
Key Opta stats
- Porto have won five of their last six home group stage games in the Champions League, losing the other.
- Galatasaray are winless in their last 12 Champions League away games, drawing two and losing 10.
- Galatasaray have failed to keep a clean sheet in any of their last 24 Champions League away games.
- Porto's Moussa Marega scored his first Champions League goal in what was his eighth appearance in the competition.
- Porto's Iker Casillas kept his 57th Champions League clean sheet, seven more than any other keeper in the competition.
O'Classico is up next for Porto, who face fellow Primeira Liga giants Benfica, while Galatasaray will look to keep hold of top spot in the Super Lig by beating Antalyaspor.