The hosts scraped a 1-0 victory in the fourth round of the competition last week, and Vitoria will be out for blood when they make the journey to Ponta Delgada on Monday.
Julio Romao's eighth-minute strike was enough for Santa Clara to dump Vitoria out of the Taca de Portugal in the round of 32 last week, with Daniel Ramos's men now set to face Moreirense in the fifth round next month.
Santa Clara's recent results in the Primeira Liga have been worrying, though, with Monday's hosts losing four of their last six in the Portuguese top flight - a run which includes three home games without a win.
Ramos has witnessed his side come up short in their last two league matches at the Estadio de Sao Miguel, although those two narrow defeats came against Sporting Lisbon and Porto, and Santa Clara were not blown away in those fixtures by any means.
Santa Clara returned to winning ways in the league with a 3-1 triumph at Nacional just before their cup tie with Vitoria, and Ramos's side currently sit seventh in the table - three points off the European places after nine matches.
Meanwhile, Vitoria's narrow defeat to Santa Clara in the Taca de Portugal was followed up with yet another cup defeat - this time to Benfica in the first round of the Taca da Liga on Wednesday.
Joao Henriques's men managed to hold the Portuguese powerhouses to a 1-1 draw after 120 minutes, but Benfica won the shootout 4-1 to condemn Vitoria to their second knockout exit in a matter of days.
Vitoria have been performing well in the league despite their cup disappointments, though, with the visitors taking the spoils in three of their last four matches in the Primeira Liga.
Belenenses are the only side to have shipped fewer goals than Vitoria's seven at this stage, and Henriques's men are notoriously strong on the road, with Vitoria aiming to win their fourth away league game in a row on Monday evening.
Vitoria - who currently occupy fifth spot in the league - will temporarily rise above Braga with a win on Monday, but Santa Clara will leapfrog the visitors if they can triumph on their own patch.
Santa Clara Primeira Liga form: LLWLLW
Santa Clara form (all competitions): WLWLWW
Vitoria de Guimaraes Primeira Liga form: WLWLWW
Vitoria de Guimaraes form (all competitions): LWWWLL
Andre Andre did not make the cut for the defeat to Benfica with gastroenteritis, but the midfielder is back in training and is expected to play a part on Monday.
Winger Marcus Edwards has recently been linked with a move back to England with West Ham United, but the 22-year-old's compatriot Jacob Maddox is doubtful with a thigh problem sustained in Wednesday's match.
Santa Clara possible starting lineup:
Pereira; Ramos, Cardoso, Villanueva, Lucas; Romao, Rashid, Lincoln; Ukra, Thiago, Carlos Jr
Vitoria de Guimaraes possible starting lineup:
Varela; Sacko, Fernandes, Mumin, Mensah; Pepelu, Andre, Almeida; Edwards, Duarte, Rochinha
We say: Santa Clara 1-2 Vitoria de Guimaraes
Santa Clara know how to beat Vitoria having already done so this season, but changes on both ends will be afoot as the two sides look to continue their charges for a European berth. The hosts' league form is questionable, whereas Henriques's men have taken 10 points from a possible 12 on the road, so we are backing Vitoria to get revenge on Santa Clara with a narrow win at the Estadio de Sao Miguel.