The primary objective was to evaluate the antioxidant and immunomodulatory efficacy of Azolla pinnata and four species of major Iraqi edible fungi, both in vitro and in vivo, using female white rats subjected to oral administration of lead acetate. Non-enzymatic antioxidant assays revealed that the reducing power increased proportionally with rising concentrations of both Azolla and fungal extracts, with 5% concentration exhibiting the highest reducing activity across all treatments. Extracts of Hericium erinaceus and Pleurotus eryngii demonstrated superior reducing capabilities, reaching values of 2.91 and 2.88, respectively. The greatest DPPH radical scavenging activity was observed at 5% concentration of H. erinaceus and P. ostreatus extracts, with inhibition rates of 58.37% and 56.25%, respectively. In enzymatic antioxidant assays, H. erinaceus extract at 5% concentration showed the highest catalase and peroxidase activities, measuring 351.27 and 2.73 units per gram of fresh tissue, respectively. Powders of H. erinaceus and Azolla at concentrations of 5%, 10%, and 15% were incorporated into the feed to assess their immunological and health efficacy in lead-intoxicated white rats. Treatment with 15% Azolla and H. erinaceus powders yielded the most favorable results in restoring immune cell homeostasis, indicated by a reduction of the neutrophil-to-lymphocyte (N/L) ratio to 1.42 and 1.33, respectively—values nearing those recorded in the control group (1.35). Lead acetate administration alone induced significant immune dysregulation, evidenced by elevated levels of pro-inflammatory cytokines IL-6 and TNF-α, reaching 22.41 pg/mL and 125.09 pg/mL, respectively. These markers were substantially reduced following treatments with Azolla and H. erinaceus, approaching physiological baseline levels, with the lowest concentrations attained at 15% dosage: 7.87 and 68.89 pg/mL for Azolla, and 5.9 and 55.67 pg/mL for H. erinaceus, respectively. Furthermore, lead exposure caused a notable decline in immunoglobulin levels (IgA, IgG, IgM, IgE) to 1.3, 6.31, 0.42, and 31.5 g/L, respectively. These levels were significantly elevated upon supplementation with Azolla (15%), reaching 2.68, 10.88, 1.28, and 60.71 g/L, and further increased with 15% H. erinaceus inclusion to 3.28, 15.06, 1.86, and 81.67 g/L, respectively. Histopathological evaluation revealed that Azolla and H. erinaceus treatments contributed to marked improvement in hepatic tissue architecture in treated rats. There was a reduction in hepatocellular degeneration and inflammation, regeneration of hepatic lobular structures with distinct cellular boundaries, as well as resolution of central vein necrosis and hemorrhage, indicating enhanced detoxification function.