Methicillin-resistance S. aureus (MRSA) possesses the ability to resist multiple antibiotics and form biofilm. Currently, vancomycin remains the last drug of choice for treatment of MRSA infection. The emergence of vancomycin-resistant S. aureus (VRSA) has necessitated the development of new therapeutic agents against MRSA. The antimicrobial and antibiofilm activities of two copper-complexes derived from Schiff base (SBDs) were tested individually, and in combination with oxacillin (OXA) and vancomycin (VAN) against a reference strain of biofilm-forming MRSA. The toxicity of the SBDs was also evaluated on a non-cancerous mammalian cell line. Compounds SBD2 and SBD4 resulted in significant reduction of biomass and metabolic activity in MRSA. However, combinations with OXA and VAN were mainly additive against the planktonic cells and cells in the biofilm. Both the compounds showed moderate toxicity against the MRC5 cell line. The selectivity index suggested that the compounds were more cytotoxic to MRSA than the normal cells. In conclusion, SBD2 and SBD4 showed antimicrobial and antibiofilm activities against the planktonic and biofilm-forming MRSA. However, the exact antimicrobial and antibiofilm mechanisms of SBD2 and SBD4 on S. aureus remain unknown.