This study analyzed post-harvest loss of sesame the case of large-scale producers in Kafta Humera district of Western Zone, Tigray region, Ethiopia. It was specifically aimed to address the research gaps by measuring post-harvest loss and analyzing its determinants of sesame produced by large-scale producers. For addressing these objectives the study used primary and secondary data obtained from field survey and desk review. Multistage sampling technique was employed to draw 126 large-scale sesame producers. Applying the simple descriptive statistics method, the percentages of sesame grain post-harvest loss were during harvesting (13.5%), drying (51.5%), un-threshed left over (17.4%), piles transportation (7%), storage (4.62%), cleaning (1.8%) that leads to the total loss of 24.6% of total production by large-scale producer. Applying multiple linear regression analysis method also, the significant determinants of post-harvest loss for large-scale farms were total sesame produced, weather condition, mode of transportation, distance of piles transported, number of stacking days, educational level, distance of farm, sesame land size amount of credit obtained, off-sesame farm income, road access, number of storage weeks and harvesting and threshing management. Depending on the results found this study recommend capacitating the large-scale producers through strengthening education, strengthening credit access at affordable interest rate, nearby farm follow up and frequently visiting of farm with effective farm management are better. For minimizing post-harvest loss it is also better if harvesting and drying technologies are introduced.