The ultimate goal of this study was to determine the influence of religious literacy and multicultural teaching competence of RME teachers on their teaching self-efficacy in the Accra Metropolis. Grounded in culturally responsive teaching and self-efficacy theory, this study employed a cross-sectional survey design. All 441 RME teachers in the eight (8) circuits in the Metropolis which has seventy-two (72) basic schools were involved in the study through the census method. Data were collected using a questionnaire and analyzed using descriptive statistics and partial least squares structural equation modeling (PLS-SEM). Findings revealed that RME teachers reported high levels of RL, MTC, and TSE. Religious literacy and multicultural teaching competence jointly explained 44.2% of the variance in TSE, with a statistically significant positive effect (p < 0.05). It was recommended that, the curriculum for training RME teachers should include in them topics on RL and MTC.