Due to its similarity in hydrophobic properties to perfluorooctanesulfonic acid (PFOS), 6:2 fluorotelomer sulfonic acid (6:2 FTSA) has emerged as a key substitute for PFOS. Its presence in aquatic environments, along with the coexistence of polyethylene terephthalate (PET), may impact the growth of aquatic plants and ecosystem stability. This study explored the changes in antioxidant defense, photosynthetic system, and metabolic responses of water hyacinths (Eichhornia crassipes) under individual and combined exposure conditions. The results indicated that water hyacinth efficiently accumulated 6:2 FTSA, with notably higher accumulation levels in leaves compared to roots, leading to a more pronounced stress response in leaves. The contents of nitrate, nitrite, ammonium, and the activities of nitrogen assimilation enzymes in leaves increased significantly, which in turn boosted the levels of reactive oxygen species (ROS) scavengers such as glutamic acid and glutathione, as well as antioxidant defense enzymes. Meanwhile, leaf photosynthesis was significantly suppressed due to the resource reallocation. This was corroborated by disruptions in the chloroplast thylakoid structure and alterations in chlorophyll fluorescence parameters. Metabolomics analysis further revealed that the contents of monosaccharides and organic acids decreased markedly, whereas amino acid levels increased significantly, suggesting that water hyacinths prioritized antioxidant defense mechanisms at the expense of growth. Additionally, we observed that the phytotoxic effects of 6:2 FTSA were exacerbated in the presence of PET nanoplastics, with the aforementioned indicators exhibiting synergistic effects. This study provides phenotypic, physiological, metabolic, and transcriptional insights into the toxic effects of the coexistence of PET nanoplastics and 6:2 FTSA on water hyacinths, offering toxicological data (e.g., oxidative stress markers and gene expression profiles) for assessing the environmental risks associated with emerging contaminants and proposing management strategies.