Background Prenatal Iron and Folic Acid supplementation is an economical way of decreasing iron and folic acid deficiency anaemia amongst expectant mothers in resource limited countries like Uganda. This study was geared toward assessing the levels of compliance to Iron and Folic Acid Supplements as well as the associated factors amongst mothers receiving prenatal services in Lira district, Uganda. Methods 252 pregnant mothers were enlisted in a cross-sectional study at Lira Regional Referral Hospital at the antenatal clinic. Adherence levels to Iron and Folic Acid Supplements were evaluated using a visual analogue scale and the associated factors were compiled through an interviewer-administered questionnaire. The findings were analyzed using SPSS software and reported in tables. Results Only 46% of the mothers attending the antenatal clinic adhered to iron and folic acid supplements over 30-day period of the previous month before the study. Participants who had good knowledge of Iron and Folic Acid Supplements before recruitment (OR 1.49 95% CI 1.12–1.97), using any reminder technique (OR 1.05; 95% CI 1.02–1.09) and being supported by their partner or relatives (OR 1.56, 95% CI 1.07–2.29) were more likely to have good adherence. Forgetfulness and fear of taking too many tablets were the main reasons for missed iron and folic acid supplements. Conclusions There was low adherence to iron and folic acid supplements among mothers attending antenatal clinic in Lira district. We recommend further investigations into the hindrances to adherence and provision of comprehensive health education to pregnant mothers.