Context: Pre-marital screening has been proven to be an effective means of reducing the overall burden of genetic disorders like Sickle Cell Disease (SCD) in the general population. Aims: To determine the knowledge, attitude and perception of traditional and religious leaders on pre-marital screening for SCD in Sokoto, North-Western, Nigeria. Settings and Design: Descriptive cross-sectional study. Methods and Material: Pre-tested interviewer administered questionnaire was administered to 375 participants selected through multistage sampling method. Data on the knowledge, attitude and perception of premarital screening for sickle cell disease were obtained. Statistical analysis used: Data were analyzed with SPSS Version 20.0. P < 0.05 was considered significant. Results: The mean age ± SD of the participants was 37.0±11.6 years and the majority of respondents were male 310 (83.1%), married 247 (67.1%) and had tertiary education 179 (50.4%). Good knowledge of SCD was demonstrated by 263 (70.1%) and positive attitude was shown by 259 (69.1%) while positive perception was received from 242 (67.9%). Age, marital and educational status were significantly associated with knowledge of SCD (p< 0.05). Knowledge of the SCD had great influence on the participant’s perception for pre-marital screening in the same way their perception influenced their attitude on pre-marital screening for SCD (p˂ 0.01). Conclusion: The traditional and religious leaders in Sokoto metropolis showed good knowledge of SCD as well as positive attitude and perception on pre-marital screening for SCD. We therefore, recommend intensive public awareness programmes and implementation of pre-marital screening of SCD as well as utilisation of the community leaders as change agents to curb the menace of SCD.