Multidrug-resistant Tuberculosis (MDR-TB) remains a global health concern. The disease results in a prolonged treatment and hence, poses a financial burden to affected individuals and their families. The Ghana National TB Control Programme (NTP) has made extensive efforts to control the menace, however, it remains a concern. This study, therefore, aimed to determine the predictors of multidrug-resistant TB in the Cape Coast Teaching Hospital of Ghana. An unmatched case-control study involving 37 cases and 111 controls was conducted using data of TB cases registered for treatment between January 2018 and December 2020 at the Cape Coast Teaching Hospital. Socio-demographic, individual level and social characteristics information were collected from respondents through telephone surveys, face-to-face interviews and review of records using a structured questionnaire built in the Kobo Collect Toolbox. The data was exported to Stata version 16.0 for analysis. Chi-square test and multiple logistic regression were used to determine the predictors of MDR-TB. Associations were considered statistically significant at a 95% confidence interval with a p-value of less than 0.05. The results revealed that the majority (25 [67.6%]) of MDR-TB cases and controls (76 [68.5%]) were aged 30 years and above with a median age of 36.5 (IQR: 28–50) years for all respondents, while 20 (54.1%) of MDR-TB cases and 33 (29.7%) of controls lived in households with one room residences for their families. The following predictors for MDR-TB were identified: BCG vaccination status (AOR = 0.17,95% CI:0.07–0.45), long distance to health facility (AOR = 4.11, 95% CI: 1.55–10.87), number of rooms in residence (AOR = 0.37,95% CI: 0.14–0.99) and first place of visit upon noticing TB symptom (AOR = 4.22,95% CI:1.31–13.64). Predictors of MDR-TB in the current study were multi-faceted. Measures to control MDR-TB should target socio-demographic, health-seeking behaviour and social-related concerns.