Background The World Health Organization has recommended daily supplementation with iron folic acid, to prevent anemias during pregnancy. However, due to many factors, compliance of pregnant women with this recommendation of iron and folic acid supplementation remains low, both in Africa and Ethiopia. Studies conducted in issue shows setting specific difference regarding determinants of iron and folic acid compliance. Objective This study aimed to assess the determinants of iron and folic acid supplementation compliance among antenatal care attendee pregnant women in the Bule Hora district, South Ethiopia, in 2024. Methods A health facility -based, unmatched case-control study was conducted in Bule Hora district from April 2024 to June 2024, via a pretested interviewer-administered questionnaire. The sample size for the study was calculated using Epi Info version 7.2.6 software. A total of 115 cases and 230 controls were included in the study. The sample size was proportionally allocated to each health facility on basis of the number of pregnant women supplemented with iron-folic acid at least one month before the data collection period; after that, systematic sampling techniques were used to select every 2nd participant from each health facility. Binary and multivariable logistic regression was conducted to identify determinants of iron folic acid compliance; AOR at a P-value < 0.05 with 95% CI was used to declare a statistically significant association after checking for the absence of multicollinearity (VIF < 1.65, tolerance > 0.6) and the Hosmer and Leme-show test of model fitness (p- value = 0.08). Results A total of 345 pregnant women were included in the study with, a 100% response rate. Prim gravidity [AOR: 4.67, 95% CI (1.60, 13.57)], antenatal care contact 4 or more times [AOR: 7.84, 95% CI (3.34-18.41)], having a husband/family support to take iron folic acid [AOR: 4.48, 95% CI (2.19-9.13)] and good knowledge on anemia [AOR: 3.79, 95%CI (1.85-7.75)] were significantly associated with iron-folic acid compliance. Conclusion This study revealed that prim-gravidity, antenatal care contact 4 or more times, having husband support, and good knowledge of anemias were determinants of good compliance. Promotion of husbands' support and frequency of antenatal care contact and provision of information about anemias are needed to increase compliance with iron folic acid.