Mandzukic, Koke to lead inexperienced Atletico
The Liga champions hold a 3-0 lead in the two-legged last 32 tie, and would set up a fixture with local rivals Real Madrid by progressing.
Simeone feels confident as he prepares to welcome third-tier L'Hospitalet to Vicente Calderon, and is ready to offer a chance to fringe players such as Jan Oblak, Jesus Gamez and Lucas Hernandez.
The Argentine has called on those coming in to grasp their opportunity in the first team, while Koke and Mario Mandzukic will be expected to lead by example.
"It is clear that tomorrow is a chance to play our fringe players and for them to showcase what they can do," he said on Wednesday. "In principle, Koke and Mandzukic will start, but you try as always to field the most competitive team to progress.
"What matters is that the guys who are having fewer minutes take the opportunity to play and get some minutes in their legs."
The fixture represents Atleti's final home match of 2014 - a year that has seen Atleti lose twice at Vicente Calderon - and Simeone is keen to finish on a high.
"The numbers speak for themselves and it has been an important year at home," he added. "Hopefully the team can close the year tomorrow in the best way and make a positive start next year."