Ivo Vieira's side face the Azoreans, who have won just one of their last seven top-flight matches, conceding 10 goals in the process.
Famalicao were unable to extend their unbeaten league run to three matches but came close as they lost 3-2 away at Portuguese giants Porto last week.
However, a penalty converted by Mehdi Taremi and a header from Marko Grujic saw the Dragons take control of the match, and although Famalicao's Anderson Silva scored in stoppage time to pull one back, the hosts were able to hold on for all three points.
That result has seen Vieira's side drop down to 14th in the Primeira Liga, just two points above the relegation playoff position and four points clear of the bottom two.
Three of Famalicao's final four league matches are against sides currently inside the top eight, including Santa Clara who they beat 2-1 away from home in January.
Famalicao have the worst home record in this season's top-flight, winning just twice and accumulating only 13 points from their 15 matches at the Municipal Stadium Famalicao.
They face a Santa Clara side who have lost eight Primeira Liga away games this campaign, including each of their last five.
The Azoreans played out an entertaining 3-3 draw against Boavista in their most recent league encounter last weekend, with Fabio Cardoso's 94th-minute equaliser giving both teams a share of the spoils at the Estadio de Sao Miguel.
Santa Clara remain in seventh place, nine points behind Pacos de Ferreira in fifth, who currently occupy the final European qualification position.
Daniel Ramos's side, who were promoted to the top-flight three seasons ago, are still on course to finish the campaign in their highest ever position, bettering 10th and ninth-place finishes in the previous two terms.
Victory on Friday would be their 11th of the season, equalling the total that they managed in both of the last two campaigns, with three matches still to play.
Famalicao left-back Ruben Vinagre missed the defeat against Porto with a thigh injury and he is unlikely to feature against Santa Clara.
Calvin Verdonk is set to keep his place in the side if the Wolverhampton Wanderers loanee fails to recover.
Famalicao possible starting lineup:
Junior; Figueiras, Riccieli, Queiros, Verdonk; Assuncao; Ugarte, Pepe; Dias, Silva, Jaime
Santa Clara possible starting lineup:
Marco; Ramos, Cardoso, Villanueva, Mansur; Lincoln, Morita, Carvalho; Carlos, Crysan, Allano
We say: Famalicao 1-1 Santa Clara
Santa Clara have little to play for as they head down the home straight, while Famalicao are still in danger of relegation and securing three points would provide a massive boost in their bid to avoid the drop.
However, with little to separate the two teams, a score draw could be on the cards at the Municipal Stadium Famalicao.