Background <p>Microplastic (MP) pollution is a growing risk to aquatic organisms. However, its chronic physiological effects on fish remains poorly described. Here we investigate that how the chronic exposure of mixed MPs affects demographics and physiology of <i>Oreochromis niloticus</i>.</p> Methods <p>We exposed fish (n = 18) for 30&#xa0;days to low-dose and high-dose concentrations of mixed MPs. Growth indices, liver biomarkers, serum markers, stress markers, oxidative stress-related enzymes, and bioaccumulation were assessed.</p> Results <p>The somatic effect of MPs was not statistically significant (<i>p</i>&gt;0.05). However, higher concentration of MPs induced a significant hepatic atrophy (<i>p</i>&lt;0.01), a decline in hepatic function (<i>p</i>&lt;0.001), hepatocellular disruption (<i>p</i>&lt;0.01), metabolic imbalance, endocrine stress, and inflammatory activation (<i>p</i>&lt;0.05-0.001), an oxidative damage and impaired defense. FTIR and stereomicroscopy further confirmed the significant bioaccumulation of polymers in muscles but traces in brain.</p> Conclusions <p>Our findings highlight subtle; yet, significant physiological risks in <i>O. niloticus</i> from chronic MP exposure.</p>