More than 24% of Nigerians are carriers of the sickle cell gene, while about 2% of all the newborns in Nigeria are born with the sickle cell disease. The disease is a lifelong cause of severe morbidity that often require prolonged hospital admission; even as the patients have 92% excess mortality. The prevention of the disease is therefore very important, especially in Nigeria whose contribution to the global total has been projected to increase. Premarital screening for the sickle cell gene is considered one of the best ways of preventing the sickle cell disease. This study assessed the knowledge, attitude and uptake of the premarital screening among married couples in Choba, a semi-urban community in south-south Nigeria. A descriptive cross-sectional study design was used, with the data collected using structured, interviewer-administered questionnaire that was administered on married male members of the study community. A total of 290 questionnaires were administered and retrieved. The respondents had an average age of 30.55 ±4.1 years; majority (65.86%) had a tertiary education and they were all Christians. All the respondents knew about the sickle cell disease, while 84.83% were aware of the premarital screening for the disease. All had positive attitude towards the premarital screening, with 88.97% recommending that the screening be made compulsory for all intending couples. Most (72.76%) of the respondents carried out the premarital screening when they got married. The age, educational attainment and the religious denomination of the respondents significantly influenced the uptake of the screening (p-value > 0.001). A total of 9.00% of the respondents were of the same HbAS genotype as their intended spouses; out of which 21.05% went ahead and got married, citing as reasons the difficulty of jettisoning their spouses (25.00%); and the power of God to prevent a child with sickle cell disease (75.00%). The knowledge, attitude and uptake of premarital screening for sickle cell disease are high in the study, even as the screening programme is not driven by the government. The input of the government is however required in providing health education, genetic counselling and prenatal diagnosis.