ObjectiveThis study aimed to determine the prevalence, spatial variation and associated factors of mixed milk feeding practice among mothers with infants aged 0–6 months in Ethiopia.Study designA cross-sectional study design was used.SettingThe study was conducted in Ethiopia.Population and participantThe study populations were mothers with infants aged 0–6 months and 550 weighted sampled mothers with infants aged 0–6 months were included in the analysis.Outcome variableThe primary outcome was mixed milk feeding practice measured by 24-hour recall assessment and the secondary outcome was factors of mixed milk feeding practice.ResultThe prevalence of mixed milk feeding practice among mothers with infants 0–6 months in Ethiopia was 55.5% with a 95% CI (51, 59). Spatial analysis revealed that mixed milk feeding practice was concentrated in Addis Ababa, Amhara, Oromia and the Southern regions of Ethiopia. Mothers with education had 1.2 times higher odds of engaging in mixed milk feeding compared with those who had no education (AOR=1.2, 95% CI 1.01, 2.3). Mothers from higher wealth index categories exhibited 1.7 times greater odds of mixed milk feeding than those from lower wealth index categories (AOR=1.69, 95% CI 1.3, 1.8). Mothers who delivered in health facilities had a 50% reduced risk of mixed milk feeding compared with those who delivered at home (AOR=0.5, 95% CI 0.3, 0.92). Lastly, the likelihood of mixed milk feeding was 2.6 times higher among mothers in urban administrative regions, while there was a 63% lower risk in less-developed regions compared with developed regions in Ethiopia.ConclusionThe study highlights the significant prevalence of mixed milk feeding practice among mothers with infants aged 0–6 months in Ethiopia. Spatial analysis revealed distinct geographical clusters of these practices, particularly in urban areas such as Addis Ababa, Amhara and Oromia. Maternal education, wealth status, place of delivery and regional differences were associated factors of mixed milk feeding. Specifically, mothers who have education and those from wealthier backgrounds were more likely to engage in mixed milk feeding, while those delivering in health facilities had a lower risk.