The home side needed penalties to see off Orlando City in the last round, while their visitors just about got the better of DC United in normal time.
Match preview
Cruz Azul managed to get the job done from 12 yards once again courtesy of a penalty-shootout victory over Orlando City after a goalless stalemate at the Inter&Co Stadium on Saturday.
In similar fashion to their group-stage clashes against Charlotte and Philadelphia Union, Martin Anselmi's men have now gone to spot-kicks in three consecutive matches, and will be confident should their round-of-16 tie follow suit.
However, Los Celestes will head into their next outing on a rough patch in front of goal having scored just twice in their last four matches since winning three straight games by a combined score of 8-0 in mid-July.
Cruz Azul have already surpassed their performance from last season's edition of this competition, where they were knocked out in the round of 32 by Charlotte following a 1-0 defeat.
Wednesday's hosts now continue their quest for a second Leagues Cup title overall and a first since going all the way five years ago in the inaugural tournament, which consisted of just eight teams at the time.
Like Cruz Azul, Mazatlan also fended off the challenge of a Major League Soccer outfit last time out, narrowly claiming a 2-1 win over DC United at Audi Field in the early hours of Saturday.
Since kicking off their Leagues Cup journey with a 1-0 defeat to New England Revolution which left them on the brink of elimination, Victor Manuel Vucetich's men have now won back-to-back matches to leave them 90 minutes away from the quarter-finals.
In that time, Los Canoneros have found the back of the net on four occasions, one more than they managed in the previous seven games, highlighting a change in attacking fortunes.
Mazatlan are yet to pick up a league win from four outings this term, but a strong cup showing could spark a resurgence for the Liga MX side who currently sit bottom but one in the standings.
Having won just one of six matches against their hosts leading up to Wednesday's trip, the visitors have it all to do if they are to emerge victorious and set up a last-eight meeting against one of Cincinnati or Philadelphia Union.
Cruz Azul Leagues Cup form:
L
W
W
Cruz Azul form (all competitions):
W
W
D
L
W
W
Mazatlan Leagues Cup form:
L
W
W
Mazatlan form (all competitions):
D
L
L
L
W
W
Team News
Twenty-five-year-old Carlos Vargas is a guaranteed absentee for Cruz Azul in this one as he is yet to fully recuperate from a broken foot.
Gabriel Fernandez is also unavailable for selection due to a long-term knee problem which has seen him fail to feature since February.
Star striker Georgios Giakoumakis has now gone four matches without finding the back of the net but is expected to lead the line once again.
Mazatlan's Hugo Gonzalez missed the win over DC United last time out through injury, and the goalkeeper is not expected to return to action on Wednesday.
This should see Daniel Gutierrez retain his place between the sticks for the second game running off the back of no starts in the nine weeks prior.
Cruz Azul possible starting lineup:
Mier; Rotondi, Piovi, Romo, Ditta, Sanchez; Torres, Lira, Faravelli; Rivero, Giakoumakis
Mazatlan possible starting lineup:
Gutierrez; Escoboza, Sanchez, Almada, Colula; Flores, Meraz; Barcenas, Del Prete, Arciga; Rubio
We say: Cruz Azul 2-1 Mazatlan
Cruz Azul have dominated this fixture to a large extent and will back themselves to get the job done on home turf.
While we expect Mazatlan to pose a stern test, we can see the hosts edging out their visitors to make it through to the quarter-finals.