Salmonella became a challenge to the global food system, from production to consumption. In this study crosssectional study- conducted from October 2018 to June2019 with the purpose of estimating the occurrence of Salmonella and to assess drug resistant profile of Salmonella isolated fromfish value chainof North West Ethiopia. Multistage sampling technique was ap- plied for selecting study districts, kebeles and landing sites. Systematic random sampling was used to sample individual fish.The muscle of fish was tested using routine biochemical tests. Data of potential risk factors were collected using struc- tured questionnaire through face-to-face interview. Data wer- eentered and analyzed using STATA version 12. The overall prevalence of Salmonella in the study area was 36.43%.Twenty five percent of Salmonella isolates showed resistance at least for one drug.Ciprofloxacin (CIP-5μg) was found the highest (9.8%) followed by Ceftazidime (CAZ-30μg), 4.88% which salmonella developed resistant from the other drugs.Factors independently predict to salmonella occurrence were pres- ence of contamination 1.1 (AOR= 1.06; 95%CI=1.04, 1.4), fish that was noticed after landing 2(AOR= 2.2; 95%CI=0.01, 5.41) and poor handling practice 2(AOR=1.8; 95%CI=0.001, 3.32). In conclusion the biochemical finding and the questionnaire survey indicated that Salmonella is widely distributed in fish harvesting in Lake Tana. hence appropriate control measures including awareness creation, code of practice, quality control measures and regular surveillance on landing sites, processing areas, processors, processing materials, retailer markets and the public in general should be implemented to mitigate the problem.