Abstract: The specific organ toxicity resulting from microplastics (MP) exposure has been extensively explored in relation to the gut, liver, testis, and lung. However, such effects are not confined to specific organs or tissues under real-world conditions. It is intriguing to ascertain whether MP exposure poses a systemic threat to the entire organism, impacting on aspects such as lifespan, sleep and fecundity. In this study, using a terrestrial animal model, Drosophila melanogaster, we showed that two doses of MP (1-5 μm) in the diet led to gut damage, with the particles retained in the digestive system. Life-long MP exposure to adult flies caused a significant reduction in lifespan. Short-term MP exposure already caused disrupted sleep structure in terms of increased sleep episode length during the day. Additionally, a week-long exposure to MP caused a reduction in ovary size, with a trend towards decreased egg-laying in mated females. Although no penetration of MP into the brain or in the ovary was observed, transcriptome analysis of Drosophila brains and ovaries showed changed gene expression patterns following MP exposure. In the ovary, Gene Ontology (GO) analysis indicated genotoxic effects on inflammation, circadian regulation, and metabolic process, with significant impacts on extracellular structure-related pathways. In the brain, GO analysis revealed changes in pathways associated with proteolysis and carbohydrate metabolism processes. Our study provides compelling evidence of negative impacts of MP exposure at a systemic level, emphasizing the need to address concerns and implement strategies to mitigate environmental pollution caused by MP.