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Introduction: neonatal mortality rate is remaining unchanged globally including Ethiopia in 2019, 54.55% of under-five death was in the neonatal period. Neonatal danger signs are predictors of neonatal death. The aim of this study was to assess mother's knowledge and health seeking practice about neonatal danger signs and its associated factors at East Belesa Woreda Northwest Ethiopia 2020. Methods: a community-based cross-sectional quantitative supplemented with qualitative study was conducted among 624 respondents. Pre-tested structured interviewer-administered data collection was applied. For qualitative semi-structured indepth interviewee guide was applied. A multi-stage sampling technique was used. Data was enteredinto epi-data version 3.1 then exported to SPSS version 23 for analysis. Binary logistic regression was used and both bivariable and multivariable regressions were done to identify the associated factors. P-value <0.05 at 95% CI was considered as a significant variable. For the qualitative part, data was transcribed then translated to write results in the form of textual form. Results: the magnitude of mothers knowledge and health seeking practice towards neonatal danger signs were found to be 37.2%, 95% CI; (33.2 - 41.0) and 73.8%, 95% CI (68.8, 78.5) respectively. Being secondary education AOR=2.79 95% CI (1.25, 6.26), Having ANC at least once [AOR=1.72 95% CI: (1.05, 2.83)] and neonates started vaccine AOR=1.84: 95% CI: (1.22, 2.76); were predictors of knowledge. Whereas institutional delivery for the current birth [AOR=1.84; 95% CI (1.03, 3.26)) and having good essential newborn care practices AOR=1.85 95% CI (1.09, 3.31) were predictors of mothers health seeking practice on neonatal danger signs. Conclusion: mother's knowledge and health seeking practices towards neonatal danger signs were found to be low. It is better to promote all mothers having ANC, delivered at health institution, starting vaccine for all neonates and address essential newborn care for all mother's special attention on mothers who were illiterate and home delivered. [ABSTRACT FROM AUTHOR]