•Co-exposure to MPs and OPFRs induced greater oxidative stress in mice.•Co-exposure to MPs and OPFRs induced greater neurotoxicity in mice.•Co-exposure to MPs and OPFRs enhanced disruption of amino acid metabolism and energy metabolism in mice. This study was performed to reveal the health risks of co-exposure to organophosphorus flame retardants (OPFRs) and microplastics (MPs). We exposed mice to polyethylene (PE) and polystyrene (PS) MPs and OPFRs tris (2-chloroethy) phosphate (TCEP) and tris (1,3-dichloro-2-propyl) phosphate (TDCPP) for 90 days. Biochemical markers and metabolomics were used to determine whether MPs could enhance the toxicity of OPFRs. Superoxide dismutase (SOD) and catalase (CAT) increased (p < 0.05) by 21% and 26% respectively in 10 μg/L TDCPP + PE group compared to TDCPP group. Lactate dehydrogenase (LDH) in TDCPP + MPs groups were higher (18%–30%) than that in TDCPP groups (p < 0.05). Acetylcholinesterase (AChE) in TCEP + PE groups were lower (10%–19%) than those in TCEP groups (p < 0.05). These results suggested that OPFR co-exposure with MPs induced more toxicity than OPFR exposure alone. Finally, in comparison to controls we observed that 29, 41, 41, 26, 40 and 37 metabolites changed significantly (p < 0.05; fold-change > 1.2) in TCEP, TCEP + PS, TCEP + PE, TDCPP, TDCPP + PS and TDCPP + PE groups, respectively. Most of these metabolites are related to pathways of amino acid and energy metabolism. Our results indicate that MPs aggravate the toxicity of OPFRs and highlight the health risks of MP co-exposure with other pollutants.