Combined contaminants of antibiotics and heavy metals in wastewater have caused global concern. Reusable flocculant CS-g-PNNPAM with different lengths of grafted thermo-responsive branches were synthesized for the removal of different types of combined contaminants (tetracycline-Cu(II), tetracycline-Zn(II), sulfadiazine-Cu (II), and sulfadiazine-Zn(II)) from wastewater. Response surface methodology was employed to study interactive effects among wastewater temperature (X-1), flocculant stock solution temperature (X-2) and flocculant dosage (X-3). The flocculation difficulty for different types of combined contaminants went with the sequence of sulfadiazine-Cu(II) < tetracycline-Cu(II) < tetracycline-Zn(II) < sulfadiazine-Zn(II), which was the opposite order of binding energies of antibiotic-heavy metals. This indicated combined contaminants with stronger binding interactions had the nature to be flocculated more easily. The optimal average length of grafted branches in the flocculant was obtained for each type of wastewater; Meantime, since it is not appropriate to manually adjust wastewater temperature (X-1) considering energy consumption aspects, operation strategies, by adjusting stock solution temperature (X-2) and flocculant dosage (X-3) to reach highest removal efficiencies of antibiotics and heavy metals, were respectively optimized for several fixed X-1 values, using statistical analysis of the results from jar tests. Finally, via a two-step method, antibiotics and heavy metals were sequentially recovered from flocs, and CS-g-PNNPAM was regenerated for further use, which follows the concepts of resource reutilization.