The big-spending club, who reached the competition's final in 2020 and semis last year, were largely outplayed in the quarter-final second leg, producing an error-strewn display while failing to trouble Mazembe. Their performance was similar to the sluggish one they produced in a 0-0 first-leg draw in Cairo.
Midfielder Kofi Kuami missed an early penalty awarded for a handball on veteran right-back Ahmed Fathi but made amends to open the scoring on 33 minutes, firing a low shot home after a dreadful blunder from central defender Ahmed Sami.
Mazembe wasted several chances and deservedly doubled their lead one minute before the break, with unmarked striker Jephte Kitambala drilling a first-timer past the keeper following a cut-back from the right hand side of the area.
Galal, who was named Egypt's new boss last week, introduced winger Ibrahim Adel and versatile midfielder Omar Gaber in the second half and Pyramids notably improved, although they could not score.
Adel and South African striker Fagrie Lakay were denied by Mazembe's keeper as Pyramids failed in their bid to win their maiden title.
Pyramids will now have to find a quick replacement for Galal as they still challenge Cairo giants Ahly and Zamalek for the Egyptian Premier League title.
Galal will now take over at the Egyptian national team following the departure of veteran Portuguese manager Carlos Queiroz.
Later on Sunday, fellow Egyptian side Masry will be eager to protect their 2-1 advantage over Morocco's RS Berkane, which they gained in Alexandria following an epic first-leg display with nine men on the field.
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