Heavy metals (HMs) pollution of soil adversely impacts agricultural productivity and poses risks to public health, necessitating regular and timely monitoring of HMs accumulation in soils. Wheat (Triticum aestivum L.), as a globally cultivated staple crop, is particularly vulnerable to HM-induced stress, which can significantly reduce its yield and quality. The purpose of the experiment was to study the effect of lead (Pb), cadmium (Cd), and arsenic (As) on the growth, photosynthetic pigments content, enzymatic and low molecular weight antioxidants, and the uptake of metals in the wheat seedlings. We carried out a pot experiment in which HMs were introduced into the soil Pb (1300 mg kg–1), Cd (20 mg kg–1), As (100 mg kg–1) separately and all together in one combination and an uncontaminated control. The doses of HMs corresponded to the registered high pollution level in impact zone (10 approximate permissible concentrations). The results showed that HMs contamination of the soil affected the growth, photosynthetic pigments and antioxidant enzymes activities in wheat. The polyelement contamination significantly reduced root growth. The polyelement contamination led to an intensification of lipid peroxidation processes, which was reflected in an increase in malondialdehyde content in leaves and roots by 39% and 127% compared with the control. The cumulative exposure affected antioxidants in wheat, leading to deregulation of defense mechanisms, characterized by an increase in reduced glutathione content in leaves and roots by 23% and 69%, an increase in proline and ascorbic acid content in leaves by 174% and 20%, and a decrease in roots by 80% and 43%, respectively. These results highlight that HMs contamination not only inhibited growth but also affected antioxidant defense system. Therefore, developing effective strategies to mitigate HMs-induced stress and enhance wheat production is crucial for sustainable agriculture in contaminated environments.