They come up against a Romania side whose players will know that victory would all but seal their place at next year's finals as one of the best third-placed teams in the group stages.
Here, Sports Mole looks at how Spain could line up for the clash.
This maxim certainly applies to the full-back role, with Moreno likely to recall first-choice right-back Dani Carvalhal alongside handing another opportunity to Valencia left-back Jose Gaya, who has impressed with his performances for club and country this term.
Another youngster who came on against Malta was Pau Torres, with the 22-year-old scoring - via his chest - moments after being introduced. The Villarreal defender is expected to partner up with Sergio Ramos in defence.
Rodri Hernandez impressed at the base of midfield against Malta, but the Manchester City midfielder will most likely be replaced by the statesmanlike Sergio Busquets, who will feel like Euro 2020 serves as his last major competition.
To see Santi Cazorla score for Spain for the first time in four years was a wonderful sight, and his performance alongside Thiago Alcantara was mesmerising as both players gave a lesson in exercising midfield control. However, the former is set to be rested in favour of handing Saul Niguez a chance to feature in the number eight role.
Moreno would have been delighted to see Friday's front three of Alvaro Morata, Pablo Sarabia and Gerard Moreno all get on the scoresheet against Malta, with the latter pair both opening their accounts at senior international level.
Their success means that the La Roja boss can encourage another front three to do the same. Dani Olmo, the star of Spain's Euro Under 21 triumph last year, was also on the scoresheet on Friday and it seems likely that he will get a chance to impress from the start alongside Paco Alcacer and youngster Mikel Oyarzabal.