Iron deficiency is a leading cause of morbidity and mortality among adolescent girls 10–19 years of age globally. Despite the free weekly iron and folic acid supplementation, prevalence of anaemia among adolescent females still between 24% to 64.6%. This study sought to identify the factors affecting the implementation of iron and folic acid program to a school-based anaemia reduction in the Nanumba South District, Northern Region, Ghana. A cross-sectional analytical study was carried out. And a simple random sampling method was used to select the schools and the adolescent girls, while purposive sampling was used to select school health coordinators and health staff. The outcome variable was IFA compliance and exposures were knowledge on anaemia and IFAS program, as well as socio-demographic factors (Age, marital status, level of education, gestational age, parity, gestation age, and occupation). Adolescent girls who consumed at least five tablets of the expected dose in the previous 7 weeks (1 tablet per week) which is equivalent to consuming 70% of the expected dose before the day of the data collection were considered compliant. Respondents who were able to get “1” in all the four knowledge questions were considered to have good level of knowledge. Occupation level of parents was self-identified by the respondents. Multivariable logistic regression analysis was performed to identify the predictors of the outcome variable. Significance level was set at p<0.05. The level of knowledge about benefits of iron and folic acid supplementation was generally high in this study (88.0%). Overall, the majority (65.7%) of the respondents complied with iron and folic acid supplementation. Father’s occupational level was the only variable, which was significantly associated with adolescent girls’ IFA consumption compliance (p=0.002). The odds of compliance among respondents who were 17-25 years was significantly 56% times lower compared to those who were 10-16 years (AOR = 0.44 (95% CI: 0.21-0.96) p = 0.038). Adolescent girls of Kokomba ethnic group were also 83% less likely to comply with iron and folic acid consumption (AOR = 0.17 (95% CI: 0.03-0.89) p = 0.036). In conclusion, the study highlighted high compliance with the IFA among respondents, emphasizing the critical roles of teachers and health workers in counseling, monitoring, and supervision, while identifying age 17-25 years and Kokomba ethnic group being less significant factors influencing compliance. It is recommended that the role of teachers and health workers in the IFAS program should be strengthened, while addressing barriers to compliance among older adolescents and engaging families.