Lead (Pb) is widely distributed in the environment that can impose potential risks to vegetables and humans. In this work, we conducted a pot experiment in Southern China to examine the physiological response and risk of edible amaranth (Amaranthus tricolor L.) under the simultaneous stresses of lead from soil and atmosphere. The results indicate that the lead content of amaranth substantially exceeded China’s national standard when Pb concentration from soils and atmosphere was high, and comparing to teenagers and adults, children exposed a higher health risk after consuming the contaminated amaranth. Under the co-stress, the lead in roots of amaranth mainly came from the soil, but the Pb from atmospheric deposition can significantly affect the lead concentration in leaves. While lead from atmospheric deposition is found to promote the growth of amaranth, the stress of lead from the soils shows an inhibitory effect, as indicated by the increase in H2O2 content, the damage in cell membranes, and the limitation in chlorophyll synthesis. The antioxidant system in stems and leaves of amaranth can effectively alleviate the Pb toxicity. However, the stress of high lead concentration from soils can substantially suppress the antioxidant enzyme activity of roots. While it is found that heavy metals in soils can significantly affect the vegetables grown in a multi-source pollution environment, we also call for the attention on the potential health risk imposed by the lead from atmospheric deposition. This study provides an important reference for the prevention and control of crop contamination in multi-source pollution environments. Display omitted •Atmospheric deposition was an important source of Pb in plant stems and leaves.•Children had higher health risks after eating Pb contaminated plants.•High concentration soil Pb stress reduced the antioxidant capacity of plants.•Plant tolerance was related to the chemical form and subcellular distribution of Pb.