Combined pollution with heavy metals and microplastics (MPs) is widespread in farmland soil, and MPs can affect the efficiency and capacity of cadmium (Cd) uptake by hyperaccumulators. However, there is a significant knowledge gap regarding the response of hyperaccumulators under such conditions. This study utilized Solanum nigrum L. (S. nigrum), a well-known Cd hyperaccumulator, to investigate the combined effects of polyethylene microplastics (PE-MPs) and Cd contamination on Cd accumulation in S. nigrum, and to systematically explore the underlying mechanisms. The results demonstrated that high doses of PE-MPs significantly inhibited S. nigrum growth and reduced Cd concentration and accumulation in plants. Meanwhile, the decrement of bioavailable Cd content and the formation of C-H and -COO in rhizosphere soil were observed with the presence of PE-MPs. The simultaneous exposure of PE-MPs and Cd caused the significant increase in the proportions of Proteobacteria and Acidobacteriota, indicating that certain PE-degrading microorganisms may play a pivotal role in aforementioned processes. More importantly, the relative abundance of the genera Pseudolabrys, DEV008, and Flavobacterium was significantly elevated, likely contributing to the response of S. nigrum to combined toxicity. Co-exposure caused a significant downregulation of biosynthetic processes, involving carbohydrates and adenosine. Additionally, the biosynthesis of ABC transporters, phenylpropanoids, flavonoids, and organic acids was also significantly affected. The findings provide a comprehensive understanding of the soil-plants ecosystem under combined pollution and provide valuable information for advancing phytoremediation strategies.