Exposure to heavy metal-contaminated vegetables, irrigation water and agricultural soil is one of the most challenging environmental issues worldwide. This study aimed to evaluate the health effects of potentially toxic metals (PTMs) including Cr, Cd, Fe, Pb, Cu, Zn, and Co from agricultural soil, irrigation water, and tomato plants collected from the Abuarie irrigation site, Northeast Ethiopia. The samples were digested using acid digestion method, and its concentration was quantified using Inductively Coupled Plasma-Optical Emission Spectroscopy. The concentrations of PTMs in the soil, tomato, and irrigation water samples ranged from 49,020 ± 275 (Fe) to 11.85 ± 0.44 (Cd), 170 ± 1.98 (Fe) to 0.29 ± 0.006 (Cd) mgkg-1, and 0.24 ± 0.003 (Fe) to 0.025 ± 0.005(Ni)mgL-1 , respectively. The results revealed Zn, Ni, Cd and Cr in soil, all metals in tomato, and Cu, Ni, Cd and Pb in irrigation water sample were above the World Health Organization threshold values. Moreover, the separate and cumulative exposure to farm soil, irrigation water, and consumption of tomato were investigated using the hazard quotient (HQ) and hazard index (HI) values, respectively. The results revealed that individual exposure to each sample type did not have a significant impact on health (HQ < 1). However, simultaneous exposure to all of the sample types (soil, tomato and irrigation water) at the same time had a high likelihood of affecting health (HI > 1). The total carcinogenic concentrations of Cr, Cd, Ni, and Pb were greater than 1 × 10-4, revealing that farmers have a high probability of developing cancer during their lifetime. Minimizing simultaneous exposure to soil, tomato, and irrigated water for local people is highly recommended to prevent the risk of PTMs.