Microplastics are posing a threat to marine ecosystems. Recent studies demonstrated that microplastics co-exposure can alter the uptake/toxicity of hazardous chemicals. In this context, this study aimed at assessing the toxicity of polyethylene (PE; 63-125 mm, irregularly-shaped), an abundant microplastic in coastal waters, and Cu-Al layered double hydroxides (LDH), a class of two-dimensional engineered nanomaterials (NM), dispersed alone or combined, in flatfish Solea senegalensis larvae. Eight-day post-hatching larvae (n=20) were exposed for 3 h to three concentrations of Cu-Al LDH (0.33, 1.0, and 3.3 mg.L-1) and PE (0.1, 1.0, and 10.0 mg.L-1) in a full factorial design (i.e., all possible combinations plus a control with only seawater), to assess histopathological and biochemical changes. The nanoclay caused no significant effects on measured endpoints. Conversely, PE (≥1 mg.L-1) triggered the activation of antioxidant defenses (CAT), neurotransmission (AChE), and aerobic energy production (ETS), without causing, however, an activation of detoxification enzymes (GSTs) or oxidative damage (LPO). The effects of PE mostly perdured in the presence of Cu-Al LDH nanoclays. The exceptions were observed in the combination of 0.33 mg LDH.L-1 X 1 mg PE L-1, which did not activate CAT, and 1 mg LDH.L-1 X 1 mg PE.L-1,which significantly increased ETS. A significant increase of the histopathological index was observed in the mixture of 1 mg LDH.L-1 X 0.1 mg PE.L-1. Nevertheless, treatments containing PE caused some degree of histopathological alterations, namely hepatic and renal hyperemia, liver hypertrophy, hepatocyte vacuolation, and gastrointestinal space dilation. PE microplastics, combined or not with Cu-Al nanoclays, seem not to compromise the homeostasis of the flatfish larvae when considering the environmental concentrations reported so far (¡ 1 mg.L-1). Yet, adverse effects can be expected if the concentration of such particles continues to rise, as projections suggest (an increment of two to four-fold by 2030).