In the day's other games, six-time winners CSKA Moscow strolled to a 91-70 home defeat of German side Bamberg and Fenerbahce Istanbul beat Croatians Cedevita Zagreb 86-73.
The match in Madrid produced almost a carbon copy of May's title showdown, when Real celebrated a record-extending ninth title with a 78-59 victory.
Olympiakos again held their own in the opening quarter before Real found another gear and prevailed thanks to solid long-range shooting.
Champions Real Madrid face uphill task after defeat
25/03/2016 AT 22:21
"I am proud how my players responded to last week's tough last-gasp defeat by Barcelona," Real coach Pablo Laso told Euroleague television.
"We always knew this was going to be a tough Top 16 section and this is a very important result for us because with nine games left, every win will matter."
Real, who improved their record to 3-2, nailed 11 of 22 three-pointers as guard Sergio Llull led the charge with 18 points and seven assists.

Real Madrid's guard Sergio Rodriguez (L) tries to score past Barcelona's guard Victor Sada during their Euroleague 2014 semi-final Four basketball game at the Mediolanum stadium in Assago, on May 16, 2014.

Image credit: AFP

The Top 16 features two groups of eight, with the top four in each section reaching the best-of-five quarter-final playoff series. The winners go into the May 13-15 Final Four in Berlin.
Olympiakos, who won successive titles in 2012 and 2013, have two wins and three defeats and face an uphill battle to avoid an early exit from the tougher of the two groups.
CSKA also clinched their third win in five games after French guard Nando De Colo made an impressive return from an ankle injury which kept him sidelined for three weeks.
De Colo netted 17 of his game-high 19 points in the first half, when the Russian giants wiped out an early 10-0 deficit to lead 55-34 at the interval.
"We made a sloppy start but after that we played better defence and I want to thank the fans for lifting the team," said CSKA's Greek coach Dimitris Itoudis.
De Colo added: "It's never easy to come back after injury but I worked on my ankle."
In the other pool, Fenerbahce racked up their fifth successive win after Italy's former NBA forward Luigi Datome scored 19 points for the Turkish side.
Forward Ekpe Udoh added 17 as the expensively-assembled hosts gave up a 15-point lead before pulling away in the final quarter.
Red Star Belgrade sink Bayern Munich to reach Euroleague Top 16
18/12/2015 AT 20:51
Euroleague holders Real Madrid advance as Maccabi Tel Aviv crash out
17/12/2015 AT 22:10