This study was conducted to develop an instructional programme on sickle cell anaemia (SCA) and test the effect of the programme on the secondary school students’ knowledge of and attitude towards sickle cell anaemia in the Jazan region of Saudi Arabia. A pretest/posttest one-arm interventional study was conducted at the Faculty of Public Health and Tropical Medicine, Jazan University, with a convenience sample of 120 male students. The intervention consisted of two interactive sessions about sickle cell anaemia and premarital screening. The mean student knowledge score was 6.04 ± 3.02 on the pretest, which improved to 10.73 ± 3.47 on the posttest, with a statistically significant difference (t = 15.2, p < 0.001). There was no significant difference in the responses pertaining to attitude before and after the health education intervention. The policy implications of these findings are discussed to improve the performance of the Saudi healthcare system in dealing with this costly inherited disease.