The escalating impact of human activities has led to the accumulation of microplastics (MPs) and heavy metals in marine environments, posing serious threats to marine ecosystems. As essential components of oceanic ecosystems, large seaweeds such as Caulerpa lentillifera play a crucial role in maintaining ecological balance. This study investigated the effects of MPs and cadmium (Cd) on the growth, physiology, biochemistry, and Cd accumulation in C. lentillifera while elucidating the underlying molecular regulatory mechanisms. The results demonstrated that exposure to MPs alone significantly promoted the growth. In contrast, exposure to Cd either alone or in combination with MPs significantly suppressed growth by reducing stem and stolon length, bud count, weight gain, and specific growth rates. Combined exposure to MPs and Cd exhibited the most pronounced inhibitory effect on growth. MPs had negligible impact while Cd exposure either alone or combined with MPs impaired antioxidant defenses and exacerbated oxidative damage; with combined exposure being the most detrimental. Analysis of Cd content revealed that MPs significantly increased Cd accumulation in algae intensifying its toxic effects. Gene expression analysis revealed that Cd exposure down-regulated key genes involved in photosynthesis, impairing both photosynthetic efficiency and energy conversion. The combined exposure of MPs and Cd further exacerbated these effects. In contrast, MPs alone activated the ribosome pathway, supporting ribosomal stability and protein synthesis. Additionally, both Cd exposure alone or in combination with MPs significantly reduced chlorophyll B and soluble sugar content, negatively impacting photosynthesis and nutrient accumulation. In summary, low concentrations of MPs promoted C. lentillifera growth, but the presence of Cd hindered it by disrupting photosynthesis and antioxidant mechanisms. Furthermore, the coexistence of MPs intensified the toxic effects of Cd. These findings enhance our understanding of how both MPs and Cd impact large seaweed ecosystems and provide crucial insights for assessing their ecological risks.