Purpose Southern region of Saudi Arabia has one of the highest prevalence of sickle cell disease and thalassemia in the kingdom. This study aims to assess the factors associated with the rejection of premarital clinical counselling in the Jazan region. Methods This is a cross-sectional investigation conducted in the Jazan region of Saudi Arabia. The investigation targeted subjects who performed premarital screening and, with their screened partners, were identified as high-risk couples and proceeded with their marriage. Data were collected via a web-based self-administered questionnaire. A section of the questionnaire targeted those who attended the premarital counselling clinic in the Jazan region and assessed the factors that led to the rejection of premarital counselling advice. Results A total of 413 participants were recruited. The mean age of the respondents was 33 years, and the majority of the respondents were female (62.5%). The majority of the respondents were related to their partners (66.8%) and were carriers of sickle cell disease (67.8%). Among the respondents, only 192 had attended premarital counselling clinics in the Jazan region. More than half of the attendees rejected the premarital counseling advice because they believed that their marriage was their unavoidable destiny. About 30% of the attendees reported that disease complications were not well explained during the counselling. Thirty-five attendees (18.2%) proceeded with the marriage because they thought the risk of transmitting the disease to their children was small and 10 attendees (5.2%) proceeded with their marriage because they believed their children’s lives would not be affected by the disease. Conclusion The findings explain the limited influence of the premarital counselling advice in raising the awareness of the attendees about inherited blood disorders. The findings indicate a strong cultural influence leading to the reduced effectiveness of premarital counselling in the Jazan region.