Meanwhile, the visitors will be looking to maintain their perfect start to the campaign following their home victory over Tondela last time out.
Match preview
Santa Clara returned to winning ways last time out when they narrowly edged out Gil Vicente 1-0 on home turf two Sundays ago.
Os Acoreanos took the lead inside the first quarter of an hour through 25-year-old forward Rui Costa before putting on a defensive show of class to keep the Gilistas at bay.
This followed a 2-0 defeat at the hands of Partizan Belgrade in the final round of the Conference League qualifiers, where Ricardo Gomes and Sinisa Sanicanin scored to turn the fixture around and seal the Serbian side's place in the maiden edition of the tournament.
The win also ended Herb Sendek's men's three-game winless run back at home, where they lost two and picked up one draw in their previous three Primeira Liga outings.
Next up is the daunting task of going against a rampant opposing side, who are unbeaten in six of the last seven meetings between the sides since 2012, picking up five wins and one draw.
Benfica, on the other hand, made it four wins from four games last time out when they saw off a resilient Tondela side 2-1 at the Estadio do Sport Lisboa e Benfica.
After falling behind to Salvador Agra's 22nd-minute opener, As Aguias upped the ante in the second half and turned the game around through goals from Rafa Silva and Gilberto.
Prior to that, Jorge Jesus's men booked their place in the Champions League group stages when they played out a goalless draw with PSV Eindhoven on August 24 to secure a 2-1 aggregate victory in the final qualifying round.
Benfica have now kicked off their campaign on a good note and will fancy their chances of unseating reigning champions Sporting Lisbon to claim their first league title since 2019.
They follow this game with a mouth-watering Champions League Group E opening game away to Dynamo Kyiv, while Santa Clara take a trip to Portimao to face Portimonense.
Santa Clara Primeira Liga form:
Santa Clara form (all competitions):
Benfica Primeira Liga form:
Benfica form (all competitions):
Team News
Santa Clara will take to the pitch without the services of 29-year-old midfielder Costinha, who trudged off the pitch injured midway through the game against Moreirense a little under one month ago.
He is joined on the sidelines by Uruguayan defender Cristian Gonzalez, who has been out of action since picking up an injury against Farense back in January.
Allano will also sit out the game after picking up a straight red last time out and in his absence Jean Patric could come in for his second starting appearance of the season.
Should that be the case, the 24-year-old forward could make up the fourth man in Ramos's preferred attacking quartet, including Lincoln, Rui Costa and Crysan.
Benfica, meanwhile, remain without the services of Portuguese defender Ferro, who sustained a muscle injury in July's friendly game against Almeria.
Jesus opted for a four-man defence against Tondela last time out, but following his side's unconvincing display, the Portuguese head coach could revert to his preferred 3-4-3 formation.
Gilberto was dropped to the bench in the aforementioned game, but after coming on to grab the winner, the Brazilian defender could be rewarded with an immediate return to the starting XI.
Santa Clara possible starting lineup:
Fernandes; Ramos, Afonso, Villanueva, Mansur; Carvalho, Morita; Costa, Lincoln, Patric; Cryan
Benfica possible starting lineup:
Vlachodimos; Lucas, Otamendi, Vertonghen; Goncalves, Gilberto, Mario, Grimaldo; Pizzi, Yaremchuk, Ramos
We say: Santa Clara 0-2 Benfica
Benfica have enjoyed a superb run of games in all competitions and have shown early signs of a proper title charge in the Primeira Liga this season.
They take on a Santa Clara side who will be looking to put together a decent run of form after picking up their first win of the season last time out.
However, we predict they will send the hosts crashing back down to earth and strengthen their lead at the top of the standings.