Iron and folic acid (IFA) consumption is an important strategy for the prevention of birth defects and anemia during pregnancy. In Ethiopia, low proportion of pregnant mothers took an iron tablet for 90 plus days. Therefore, the aim of this study was to assess compliance to IFA consumption and its associated factors among mothers attending antenatal care in Southern Ethiopia, 2021. An institution-based cross-sectional study triangulated with qualitative methods was conducted. The data was collected data from 378 respondents selected by a simple random sampling technique and 21 in-depth interviews were conducted. Epi Data version 3.1 was used to enter data, which was then exported to Statistical Package for the social Science (SPSS) version 21 for further processing and analysis. Bivariable and multivariable logistic regression analyses were carried out to identify the significant association. Variables with a P-value of less than 0.05 were considered significant. The Open code software version 4.03 was used to code and categorize qualitative data, and then thematic analysis was employed to qualitative data. The compliance rate of IFA consumption was 66.58% 95% CI: 61.5-71.4%) Maternal education (AOR: 3.01, 95%CI:1.29, 6.35), knowledge about anemia (AOR: 2.63, 95% CI:1.29), 5.37), knowledge about IFA (AOR: 2.95, 95% CI (1.45, 6.02)), ANC visits (AOR: 2.70, 95% CI 1.17, 6.22), fear of side effect (AOR: 0.08, 95% CI:0.02, 0.24), registration time for initiation of ANC visits (AOR:4.63, 95% CI:1.50, 14.26), and counseling on IFA (AOR:3.95, 95% CI:1.57, 9.98) were significantly associated with compliance IFA consumption of the pregnant mothers. Supplement-related, pregnancy and experience-related, facility related, behavioral -related, perceived family support, and perceived cultural belief findings were identified from qualitative study. In this study, the compliance with IFA consumption was low and influenced by huge range factors. To improve compliance with IFA, health workers provide proper counseling and education for pregnant women on IFA and follow up supplementation.