Microorganism biotransformation of sulfamethazine (SMT) in aqueous environments is a major concern, especially considering their exposure to coexisting SMT and heavy metals. Phanerochaete chrysosporium (P. chrysosporium) is a more concerned Cadmium (Cd) and SMT hyper accumulation specie. This study, referring to metabolic mechanisms and application, was performed to investigate the single and combined effects of Cd-SMT, including toxicity, resistance, as well as the accumulation and biotransformation by P. chrysosporium. The results revealed that Cd-SMT co-contamination caused increasing active oxygen accumulation, and the number of antioxidant enzyme and non-enzymatic antioxidants were higher than that under the stress of their individual pollution. It was found that P. chrysosporium accumulated high levels of Cd with the increment of 6.98-23.96% induced by Cd-SMT co-contamination compared to under the stress of Cd individual pollution. What's more, the addition of Cd reduced the toxicity of SMT to P. chrysosporium. The decrease of malonaldehyde and the increase of protein also proved that P. chrysosporium held enormous potential to fit in the co-contaminated environment, and to remediate the co-contaminated water especially in the long-term treatment. These results undoubtedly contribute to the development of fungi-based technologies and the applications of P. chrysosporium in realistic environment rather than laboratory simulation environment.