The aim of current study was to investigate the epidemiology of Hepatitis E virus (HEV) in humans and geographically matched food animals as a novel zoonotic assessment in Egypt. Blood samples were collected from patients who had a history of jaundice and attended to fever and general hospitals. Animal blood samples were collected from cows, buffaloes, sheep and goats convenient to HEV seropositive humans. Enzyme Immuno Assay (EIA) protocol was used to determine IgG anti-HEV. Sex and pregnancy were investigated as potential risk factors for HEV infection. Of 134 examined humans, 51 (38.1%) were positive for IgG anti-HEV. The males showed 26.8% seropositivity while the recorded female seropositivity was 50.8%, with a significant difference at P = 0.005, Odds Ratio (OR) = 0.35 at 95% confidence interval (CI): 0.17–0.73. There was a significant difference at P = 0.02 between seropositivity in pregnant (25%) and non-pregnant women (59.6%); OR was 0.23 (95% CI: 0.06–0.81). Anorexia was the most common symptom whereas paraesthesia and back pain were the least within icteric seropositive HEV humans. Hepatitis E virus seropositivity was recorded in 21.6%, 14%, 4.4% and 9.4% from examined cows, buffaloes, sheep and goats, respectively. The infected food animals were convenient to positive HEV humans who may declare the epidemiological picture of potential zoonotic HEV.