Both Isco and Asensio, part of Spain's faltering World Cup campaign in Russian Federation, had not started any of first seven games under new club manager Santiago Solari but were included in a highly-rotated clash against the third-tier side.
Real Madrid have quietened down the whispers surrounding star midfielder Isco's exit in the January window by demanding clubs meet his release clause which stands at a whopping €700m.
"I am thrilled for Isco, for his two goals and it is a shame about the other one that the goalkeeper kept out".
A much-changed Real Madrid put six goals past Melilla in the Copa del Rey in midweek
Melilla, a tiny Spanish autonomous enclave in north Africa, managed to give their travelling supporters something to celebrate when striker Yacine Qasmi smashed a penalty beyond Navas in the 81st minute.
Nacho is out for Real Madrid, though they should be able to start a full-strength backline.
Ballon' d'Or victor Luka Modric, Gareth Bale, Sergio Ramos, Raphael Varane, Karim Benzema and Thibaut Courtois are all expected to return to Solari's starting XI after sitting it out in midweek.
Mariano Diaz went off near the end because of an apparent muscle injury, while Madrid youth players Fran Garcia and Alvaro Fidalgo came on for their debuts as second-half substitutes.
Levante defeated second division Lugo 2-0 to advance 3-1 on aggregate.
Athletic Bilbao repeated the 4-0 result from the first leg against Huesca to advance 8-0 overall.
Wednesday night saw Barcelona, Atletico Madrid, Sevilla and Valencia all book their places in the last 16 with the draw to be made on Friday.