<p>The ubiquitous presence of micronanoplastic (MNP) pollution raises significant concerns regarding its potential impact on human health. This review synthesizes current evidence on the detrimental effects mediated by the MNP–immune axis across various organ systems. We explore the primary routes of MNP entry into the human body – inhalation, ingestion, and dermal contact – and their subsequent cellular interactions, including uptake mechanisms and cytotoxicity. Furthermore, we examine the immunomodulatory effects of MNP exposure in key organ systems, including the nervous, endocrine, integumentary, reproductive, respiratory, skeletal, cardiovascular, and digestive systems in human, animal, and in vitro models. Our analysis highlights the capacity of MNPs to induce oxidative stress, trigger inflammation, and disrupt immune homeostasis, potentially contributing to a range of adverse health outcomes such as neuroinflammation, endocrine disruption, skin damage, reproductive dysfunction, respiratory illnesses, bone degradation, cardiovascular disease, and gut microbiota alterations. We also propose an algorithm to guide future research on the MNP–immune axis. Understanding the intricate interplay between MNP and the immune system across different organs is crucial for assessing the full spectrum of human health risks associated with microplastic pollution and for developing effective mitigation strategies.</p>