The focus of this study was to determine the influence of religious literacy and multicultural teaching competence on the teaching self-efficacy of Religious and Moral Education (RME) teachers in public basic schools within the Kumasi Metropolis. The research employed a cross-sectional survey design with a sample of 308 RME teachers selected through the stratified sampling technique from 165 basic schools across 14 circuits. Data were collected using questionnaires and analysed using Partial Least Squares Structural Equation Modelling (PLS-SEM). The findings revealed that religious literacy significantly and positively influenced teachers’ self-efficacy (β = 0.487, p < 0.05), accounting for 23.7% of the variance. Similarly, multicultural teaching competence demonstrated a strong positive effect on teaching self-efficacy (β = 0.711, p < 0.05), explaining 50.6% of the variance. Finally, the study found that religious literacy and multicultural teaching competence together contributed 52.2% to RME teachers' teaching self-efficacy (SD = 0.692, p < 0.05, R² = 0.522). The study recommended that the Ghana Education Service (GES) and the National Council for Curriculum and Assessment (NaCCA) should design and mandate regular in-service training programmes focused specifically on religious literacy for RME teachers. Also, it was recommended that pre-service and in-service training should emphasise awareness of personal biases, deep knowledge of learners’ cultural and religious backgrounds, and practical skills for culturally responsive pedagogy.