Background Farmers in developing countries, including Ethiopia, are exposed to agricultural pesticides, including pesticides that are restricted or banned in developed countries. There is little information available on pesticide use safety practices and associated factors among Ethiopian farmers, particularly in the study area. Objective To assess pesticide use safety practices and associated factors among farmers in Fogera district wetland area, Amhara region, Northwest Ethiopia. Methods A community-based cross-sectional study design that employs quantitative and qualitative methods was used from August 25 to September 30, 2021. Four hundred thirty participants were included by using a stratified random sampling technique. Pre-tested interview questionnaires, observational checklists, and key informant and in-depth interview guides were used to collect data. The quantitative data were collected by face-to-face interviews of farmers, whereas the qualitative data were collected by in-depth interviews of selected farmers and key informant interviews of responsible stalk holders. The data were entered into Epi data version 4.6 and analyzed using SPSS version 21. Bi-variable logistic regression was used to identify factors associated with the dependent variable. A p-value of less than 0.05 was used as a cut-off point to declare a statistically significant association between factors and outcome variables. The odds ratio and 95% CI were calculated to describe the strength of the association between factors and outcome variables. The qualitative study included 35 respondents from various backgrounds and levels of expertise, which were analyzed using thematic analysis by open-code 4.03 version software. Result The proportion of good pesticide use safety practices in the study area was 24.4% (95% CI: 21.4%–29.3%). Educational status (adjusted odds ratio (AOR): 3.19, 95% CI: 1.44–6.71), experience of pesticide spraying (AOR: 6.85. 95% CI: 2.426–9.35), knowledge of pesticide usage (AOR: 3.40, 95% CI: 1.459–7.855), access to safety materials (AOR: 2.06, 95% CI: 1.198–3.536), and ever having received training (AOR: 4.93, 95% CI: 2.88–8.59) were factors associated with good safety practice in pesticide use. Qualitatively, limited material access, lack of government attention, insufficient training opportunities, absence of media coverage, weak enforcement of laws, and limited guideline access barred good safety practices for pesticide use. Conclusion The study revealed that good safety practices were low in the study area. Being educated, having experience with pesticide spraying, having good knowledge of pesticide usage, having access to safety materials, and having received pesticide use training all increased the likelihood of good pesticide use practice. Insufficient training opportunities and material access, weak law enforcement, limited access to guidelines, and a shortage of media coverage were challenges identified qualitatively.