Mycobacterium avium subspecies paratuberculosis (MAP) is a chronic granulomatous intestinal disease and causative agent of Johne’s disease (JD) in domestic and wild ruminants. This study explores the intricate dynamics of the host immune response in MAP infection and its implications for disease progression and control. Our investigation revealed the pivotal role of interleukin-10 (IL-10) in mediating the communication between the host’s innate and adaptive immunological responses. IL-10 inhibits interferon-gamma (IFN-γ) secretion, altering the balance between Th1 and Th2 responses. In the early stages, a robust Th1 response marked by increased IFN-γ production is observed, but as the disease progresses, a shift towards a humoral Th2 response occurs. Furthermore, we found that IL-10 exerts suppressive effects on macrophage (Mφ) anti-mycobacterial action, leading to increased intracellular survival of mycobacteria. IL-10 also hampers Mφ antimicrobial activity by suppressing the production of essential cytokines such as IL-12 and tumor necrosis factor alpha (TNF-α), crucial for activating natural killer (NK) cells and inducing differentiation of CD4+ T lymphocytes into Th1 effector cells. Importantly, our study sheds light on the intricate interplay between past infections or concurrent active co-infections and their influence on the immune response to unrelated pathogens in the context of paratuberculosis. This review underscores the multifaceted role of IL-10 in the immunopathological manifestation of MAP infection and host immunomodulation. These findings provide valuable insights for both animal and human research in the fight against MAP infection, emphasizing the importance of balancing immune responses and considering the influence of concurrent infections in disease progression.