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Culture is a strong determinant of food security through its influence on what society considers acceptable for consumption. Karamoja sub-region is one of the most ethnically diverse parts of eastern Africa, and is associated with the highest levels of food insecurity in Uganda. However, there is a general lack of understanding on the extent to which ethnicity is a contributing factor to food insecurity. We examined the relationship between ethnicity and food security in relation to commonly practiced cultural norms among the Jie, Karamojong and Tepeth ethnic groups of Karamoja. Data from 273 randomly selected households across a range of cultural settings were obtained using structured questionnaires in the September-October (2015) period. Food security status was assessed using the Household Food Insecurity Access Scale (HFIAS), daily calorie intake and coping strategy index. The study also used focus group discussions to assess the implications for food security of common cultural practices. Results confirm the general observation that the sub-region is food insecure. There were also significant variations in food security across geographical location and ethnicity. Cultural restrictions, applied particularly to women and children, over the consumption of several nutritious foods from livestock were revealed. Consumption of raw milk and animal blood, potential sources of food-borne infections and thus of malnutrition, was found to be high in the sub-region and varied significantly across ethnicity. The findings provide a basis for interventions aimed at reducing food insecurity and averting cultural impediments to a more nutritious diet.