<p>Phytoremediation using native macrophytes offers a sustainable approach to improving domestic wastewater (DW) quality while promoting ecological balance. This study evaluated the phytoremediation potential of <i>Schoenoplectus americanus</i> (Pers.) Volkart ex Schinz and R. Keller under mesocosm-scale conditions simulating real environmental settings. The removal efficiency of key physical, chemical, microbiological, and organoleptic parameters was assessed, alongside the plant’s physiological, biochemical, and metabolomic responses. After 30&#xa0;days of treatment, <i>S. americanus</i> achieved significant reductions in contaminants, including 97% of total phosphorus, 85% of chemical oxygen demand, 82.5% of total nitrogen, and near-complete removal of total coliforms (from 2 × 10⁶ to 7 × 10² NMP/mL) and mesophilic aerobic bacteria (from 3 × 10⁶ to 4 × 10³ UFC/mL). Moreover, the treated water exhibited clear improvements in odor and color. Physiological analyses revealed stable osmotic potential and membrane permeability, while increases in photosynthetic pigments, primary metabolites, and abscisic acid levels indicated adaptive responses to abiotic stress conditions. Gas chromatography–mass spectrometry analysis identified secondary metabolites, such as 13-docosenamide, potentially involved in enhancing plant–microbe interactions and nitrogen metabolism. Overall, <i>S. americanus</i> demonstrated high resilience and efficiency in DW treatment, supporting its integration into nature-based treatment solutions such as floating wetlands. These systems represent a sustainable and scalable approach with clear applicability to real-world wastewater treatment, particularly in settings lacking conventional infrastructure.</p> Graphical Abstract <p></p>