This study aims to understand the effect of inoculation by arbuscular mycorrhizal fungi Glomus intraradices (AMF) on the regulation of carbon and nitrogen sensibility and the antioxidant system in Sorghum bicolor (L.) Moench plants under lead (Pb) stress (750 ppm). Plant morphology, accumulation of lead, IAA, H2O2, MDA, and chlorophyll contents were assayed. The enzymes involved in the carbon/nitrogen interaction as well as the antioxidant enzymes were evaluated via a two-factor pot experiment (inoculation by AMF and stress by Pb). AMFs attenuate Pb damage by upregulating the antioxidant system: superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione s-transferase (GST), and glutathione reductase (GR). Similarly, the activity of each of the key enzymes responsible for the interaction of nitrogen and carbon metabolic pathways, glutamine synthetase (GS), glutamate dehydrogenase (GDH), phosphoenolpyruvate carboxylase (PEPC), and aspartate aminotransferase (AAT), were measured and showed a significant increase in mycorrhizal plants. AMF inoculation decreased H2O2 and MDA content and increased the indole acetic acid (IAA) content, which indicates that mycorrhizal inoculation has a great ability to attenuate Pb resistance. Pb stress also negatively affected plant growth by disrupting carbon and nitrogen enzymatic pathways as well as the antioxidant system. Therefore, inoculation with AMFs reduced Pb fullness by decreasing its accumulation in sorghum leaves and roots and regulating the enzymatic system involved in plant growth.