Plastic pollution and invasive species are recognised as pervasive threats to marine biodiversity. However, despite the extensive on-going research on microplastics’ effects in the biota, knowledge on their combination with additional stressors is still limited. This study investigates the effects of polyamide microplastics (PA-MPs, 1 mg/L), alone and in combination with the toxic exudate from the invasive red seaweed Asparagopsis armata (2%), after a 96 h exposure, in the mussel Mytilus galloprovincialis. Biochemical responses associated with oxidative stress and damage, neurotoxicity, and energy metabolism were evaluated in different tissues (gills, digestive gland, and muscle). Byssus production and PA-MP accumulation were also assessed. Results demonstrated that PA-MPs accumulated the most in the digestive gland of mussels under PA-MP and exudate co-exposure. Furthermore, the combination of stressors also resulted in oxidative damage at the protein level in the gills as well as in a significant reduction in byssus production. Metabolic capacity increased in both PA-MP treatments, consequently affecting the energy balance in mussels under combined stress. Overall, results show a potential increase of PA-MPs toxicity in the presence of A. armata exudate, highlighting the importance of assessing the impact of microplastics in realistic scenarios, specifically in combination with co-occurring stressors, such as invasive species.