Replacing Roberto Mancini at the helm, Spalletti heads into September's fixtures without a trio of Euro 2020 heroes in Leonardo Bonucci, Marco Verratti and Jorginho, while Domenico Berardi and Gianluca Scamacca are other notable absentees.
One area where there will seemingly be no alterations for a while is in goal, where Paris Saint-Germain number one Gianluigi Donnarumma is set to make his 55th appearance for the Azzurri aged just 24.
Giovanni Di Lorenzo and Federico Dimarco are reportedly set to get the nod in the full-back positions, while Alessio Romagnoli ought to fend off Gianluca Mancini to partner Alessandro Bastoni.
Newcastle United new boy Sandro Tonali is a shoo-in for a midfield start alongside Inter Milan's Nicolo Barella, but Spalletti may be facing more of a quandary for the final spot in his engine room trident.
Bryan Cristante, Manuel Locatelli and Lorenzo Pellegrini are all capable options, but Inter new boy Davide Frattesi - who scored in June's Nations League third-placed playoff win over the Netherlands - may earn another opportunity to impress.
Up top, skipper Ciro Immobile will aim to consign his injury woes to the past and build on a tally of 16 goals from 56 international appearances, likely with Matteo Politano and Federico Chiesa alongside him.
Italy possible starting lineup: Donnarumma; Di Lorenzo, Romagnoli, Bastoni, Dimarco; Barella, Tonali, Frattesi; Politano, Immobile, Chiesa