Microplastics contamination of the aquatic environment is considered a growing problem. The ingestion of microplastics has been documented for a variety of aquatic animals. Studies have shown the potential of microplastics to affect the bioavailability and uptake route of sorbed co-contaminants of different nature in living organisms. Persistent organic pollutants and metals have been the co-contaminants majorly investigated in this field. The combined effect of microplastics and sorbed co-contaminants in aquatic organisms still needs to be properly understood. To address this, we have subjected zebrafish to four different feeds: A) untreated feed; B) feed supplemented with microplastics (LD-PE 125–250 μm of diameter); C) feed supplemented with 2% microplastics to which a mixture of PCBs, BFRs, PFCs and methylmercury were sorbed; and D) feed supplemented with the mixture of contaminants only. After 3 weeks of exposure fish were dissected and liver, intestine, muscular tissue and brain were extracted. After visual observation, evaluation of differential gene expression of some selected biomarker genes in liver, intestine and brain were carried out. Additionally, quantification of perfluorinated compounds in liver, brain, muscular tissue and intestine of some selected samples were performed. The feed supplemented with microplastics with sorbed contaminants produced the most evident effects especially on the liver. The results indicate that microplastics alone does not produce relevant effects on zebrafish in the experimental conditions tested; on the contrary, the combined effect of microplastics and sorbed contaminants altered significantly their organs homeostasis in a greater manner than the contaminants alone.