Biofilm infections are associated with a high mortality risk for patients. Antibiotics perform poorly against biofilm communities, so high doses and prolonged treatments are often used in clinical settings. We investigated the pairwise interactions of two synthetic nano-engineered antimicrobial polymers (SNAPs). The g-D50 copolymer was synergistic with penicillin and silver sulfadiazine against planktonicStaphylococcus aureusUSA300 in synthetic wound fluid. Furthermore, the combination of g-D50 and silver sulfadiazine showed a potent synergistic antibiofilm activity againstS. aureusUSA300 using in vitro and ex vivo wound biofilm models. The a-T50 copolymer was synergistic with colistin against planktonicPseudomonas aeruginosain synthetic cystic fibrosis medium, and this pair showed a potent synergistic antibiofilm activity againstP. aeruginosain an ex vivo cystic fibrosis lung model. SNAPs thus have the potential for increased antibiofilm performance in combination with certain antibiotics to shorten prolonged treatments and reduce dosages against biofilm infection.