Meanwhile, their third-tier hosts head into this contest determined to back up their famous triumph over Real Madrid last week.
Four victories from five matches and winning the Supercopa de Espana with triumphs over Real Madrid and Barcelona is far beyond what Marcelino would have realistically expected when arriving at San Mames.
Nevertheless, the Spaniard will hope that the recent successes are a sign of things to come as he bids to make progress in La Liga and the Copa del Rey.
Sitting four points adrift of seventh position with a game in hand, achieving a Europa League spot through the league will feel the easier of those two tasks.
However, with Real Madrid and Atletico Madrid already out of this competition, Marcelino is aware that Athletic will not have a better chance of ending their 27-year wait for their 24th Copa del Rey.
Los Leones prepared for this game with a 5-1 victory over Getafe on Monday night in a game which saw Raul Garcia record his second double in three appearances.
While Athletic are the clear favourites to prevail at Estadio El Collao, there is little chance of any complacency after Alcoyano's efforts last week.
Real were on course for victory when holding a 1-0 advantage with 10 minutes remaining, but late goals in normal time and extra time secured the biggest win in their history.
The result was all the more remarkable due to Juanan's decisive goal coming shortly after Alcoyano had been reduced to 10 men in the closing stages of the additional 30 minutes.
With a win over Huesca also being recorded in the previous round, Vicente Parras and his squad will be confident of claiming a third successive La Liga scalp.
The third-tier side have put together a nine-match unbeaten streak in all competitions, registering five clean sheets and conceding just four goals.
Alcoyano Copa del Rey form: WWW
Alcoyano form (all competitions): WWWDWW
Athletic Bilbao Copa del Rey form: W
Athletic Bilbao form (all competitions): WLWWWW
Having just a three-day turnaround since the win over Getafe should lead to Marcelino making several alterations to his side.
Parras could revert back to the team which performed so well against Real in the last 32.
Mourad El Ghezouani, who is on loan from Elche, should come back into the attack after only being used as a substitute against Orihuela.
Alcoyano possible starting lineup:
Juan; Sanchez, Ferriz, Gonzalez, Carbonell; Rubio, Jony, Juanan, Lopez; Mourad, Mejia
Athletic Bilbao possible starting lineup:
Simon; Capa, Nunez, Alvarez, Lekue; Marcos, Lopez, Vesga, Berenguer; Williams, Villalibre
We say: Alcoyano 1-4 Athletic Bilbao
Marcelino will make changes for this contest, something which will provide a window of opportunity for their hosts. Nevertheless, we still expect Athletic to record a dominant win, keeping them on course to win a second piece of silverware at the end of the season.