The coexistence of polystyrene (PS) and polypropylene (PVC) microplastics (MPs) and methamphetamine (METH) in aquatic systems is evident. However, the joint toxicity is unclear. Here, zebrafish larvae were exposed to single PS and PVC MPs (20 mg L−1) and combined with METH (250 and 500 μg L−1) for 10 days. The results indicated that acute exposure to PS and PVC MPs induced lethal effects on zebrafish larvae (10–20%). Treatment with MPs markedly suppressed the locomotion of zebrafish, showing as the lengthy immobility (51–74%) and lower velocity (0.09–0.55 cm s−1) compared with the control (1.07 cm s−1). Meanwhile, histopathological analysis revealed pronounced depositions of MPs particles in fish’s intestinal tract, triggering inflammatory responses (histological scores: 1.6–2.0). In the coexposure groups, obviously inflammatory responses were found. Furthermore, the up-regulations of the genes involved in the oxidative kinase gene and inflammation related genes implied that oxidative stress triggered by MPs on zebrafish larvae might be responsible for the mortality and locomotion retardant. The antagonistic and stimulatory effects of METH on the expression changes of genes found in PVC and PS groups implied the contrary combined toxicity of PS/PVC MPs and METH. This study for the first time estimated the different toxicity of PS and PVC MPs on fish and the joint effects with METH at high environmental levels. The results suggested PS showed stronger toxicity than PVC for fish larvae. The addition of METH stimulated the effects of PS but antagonized the effects of PVC, promoting control strategy development on MPs and METH in aquatic environments.