Reproductive abnormalities are common in human population who were exposure of harmful substances such as lead. In the present work, the harmful effects of lead on the immunomodulation of testicular macrophages were experimentally investigated. Macrophages constitute the innate immune system, which is crucial for the host's defense mechanism. When testicular macrophages were exposed to lead (in vitro), there was a significant change in their morphology (16.2 ± 0.44%) between the control group and the lead poisoning group (82.48 ± 1.2%). The modified morphology thus affects the phagocytic index of testicular macrophages, making them ineffective in elimination of invasive microorganisms. Myeloperoxidase, an important enzyme produced by macrophages which are responsible for the oxidative elimination of invasive microorganisms, is also observed to be inhibited in lead exposed testicular macrophages (12.7 ± 0.2 μM) to (78.6 ± 1.4 μM). Macrophages from lead intoxicated testes significantly reduce nitric oxide release, a key cellular signaling enzyme released in response to external stimuli. This in turn affects the pro-inflammatory cytokine TNF-α and IL-6, which are important in maintaining the testicular immune response. These results indicate that lead significantly affects testicular macrophage shape, innate immune responses, enzyme release and proinflammatory response leading to reproductive failure in male Swiss albino mice.