The striker’s club team-mate Fabregas does not feature, having struggled to break into the Stamford Bridge starting XI under Antonio Conte, while Lopetegui prefers Sevilla stopper Sergio Rico over Casillas for games against Italy and Albania.
Andres Iniesta will lead Spain after returning from a knee injury.
Spain will be seeking to avenge a loss to Italy at the European Championship that ended the team’s bid for a third consecutive continental title.
Lopetegui named Iniesta in his squad on Friday for the away qualifiers on October 6 and October 9.
‘The return of Andres is very good news for us,’ Lopetegui said. ‘He has played consistently for the past month. We are happy he is here, above all given the rivals we have to face.’
The most notable inclusion was Napoli forward Jose Callejon in place of new Barcelona striker Paco Alcacer, who was dropped.
He will join an attack consisting of Costa, Alvaro Morata, Nolito and Vitolo.
Midfielder Isco is involved while Madrid defender Nacho Fernandez is also back.
The 2-0 loss to Italy in the last 16 at Euro 2016 marked the end of Vicente del Bosque’s long and successful stint as Spain’s manager.
Lopetegui has since been tasked with rejuvenating a team that won the 2010 World Cup and 2008 and 2012 European Championships.
Under Lopetegui, Spain beat Lichtenstein 8-0 in their first qualifier after seeing off Belgium in a friendly.
‘These are two important matches, but they are not definitive,’ Lopetegui said.
‘We know how tough they will be and we are motivated to meet the challenge. We will not settle for draws.’
Goalkeepers: David de Gea (Manchester United), Pepe Reina (Napoli), Sergio Rico (Sevilla).
Defenders: Nacho Fernandez (Real Madrid), Jordi Alba (Barcelona), Dani Carvajal (Real Madrid), Sergio Ramos (Real Madrid), Gerard Pique (Barcelona), Javi Martinez (Bayern Munich).
Midfielders: Koke (Atletico Madrid), Sergi Roberto (Barcelona), Saul Niguez (Atletico Madrid), Sergio Busquets (Barcelona), David Silva (Manchester City), Lucas Vazquez (Real Madrid), Thiago Alcantara (Bayern Munich), Andres Iniesta (Barcelona), Isco (Real Madrid).
Forwards: Jose Callejon (Napoli), Vitolo (Sevilla), Alvaro Morata (Real Madrid), Diego Costa (Chelsea), Nolito (Manchester City).