Micro- and nanoplastics (MNPs) are increasingly recognized as emerging contaminants of concern for human health. Their small size, diverse composition, and reactive surface enable interactions with biological barriers and cellular systems. This comprehensive narrative review synthesizes and critically evaluates current evidence on the mechanistic effects of MNPs in humans and experimental models. Systemic mechanisms, including oxidative stress, inflammation, barrier disruption, and immune dysregulation, may underlie reported adverse effects in the gastrointestinal tract, cardiovascular, nervous and reproductive systems, as well as the placenta. Omics studies further reveal alterations in metabolic and stress-response pathways, providing systems-level insights and candidate biomarkers. Human data remain limited to biomonitoring studies, and causality has not yet been established. Toxicological data, though informative, often rely on pristine particles and high-dose, short-term exposures that exceed environmental estimates, highlighting the need for chronic, low-dose models. Major challenges include difficulties in detecting and quantifying MNPs in tissues, limited attribution of effects to polymers versus additives or adsorbed contaminants, and lack of standardized characterization and reporting. Emerging advances, such as reference materials, omics profiling, and organ-on-chip technologies, offer opportunities to close these gaps. Overall, the available data suggest biologically plausible pathways for health risks, but methodological refinement and harmonized research strategies are essential for robust human health assessment.