Background: Iron deficiency anemia is a prevalent and major public health problem in low- and middle-income countries among adolescent girls. The risk of Iron deficiency anemia and its consequences are prevented by taking and complying with a weekly iron-folic acid supplement. However, there was no information regarding compliance and its associated factors in Ethiopia. The study aimed to determine the magnitude of compliance with weekly Iron-folic acid supplementation and associated factors among Jimma Arjo secondary school adolescent girls. Methods: Institutional-based cross-sectional study was conducted on 417 adolescent girls in three secondary schools of Jimma Arjo, West Ethiopia from March 1st to 31st, 2022 using interviewer-administered structured and semi-structured questionnaires. Bivariable and multivariable logistic regression analyses were used to determine the association of variables. Results: Compliance with iron-folic acid supplementation was 29.3% with 95% CI (24.9, 33.3). Mother`s secondary level of education (AOR=4.94 (95% CI:2.45,9.94)), awareness of anemia (AOR=4.23 (95% CI:2.35,7.61)), good knowledge about iron-folic acid supplementation (AOR=3.96 (95% CI:2.17,7.22)), lack of iron-folic acid supplementation (AOR=0.42 (95% CI:0.23,0.75)), and iron-folic acid supplementation side effects (AOR=0.17 (95% CI:0.08,0.37)) were factors significantly associated with iron-folic acid supplementation compliance. Misconceptions about iron-folic acid supplementation, forgetfulness of tablet, lack of access to drinking water, and irregularity of school weekly iron-folic acid supplementation days were identified as the main barriers to adolescent girls' compliance with iron-folic acid supplementation in a qualitative study. Conclusions: Weekly iron-folic acid supplementation compliance was low at 29.3%. Scheduled health education, parental participation in the program, access to drinking water, refresher training for school focal persons, and fixed weekly iron-folic acid supplementation days can improve compliance with iron-folic acid supplementation and are recommended.