This study was undertaken to determine the antibacterial activity and interactive effects of the methanol, ethanol and aqueous extract ofAndrographis paniculataandPiper betleleaves with amoxicillin against selected clinical isolates of respiratory pathogens:Escherichia coliUSTCMS 1030,Pseudomonas aeruginosaUSTCMS 10013, andStaphylococcus aureusUSTCMS 1097. Antibacterial activity of the plant extracts using disk diffusion showed that the methanol extract ofP. betleexhibited inhibitory activity against all the test organisms, whereas the methanol and ethanol extracts ofA. paniculataexhibited antibacterial activity toS. aureusUSTCMS 1097 only. The antimicrobial properties of each plant extract were further evaluated using broth microdilution. Results showed that the ethanol extract ofP. betlehad the most potent antibacterial activity against all test bacteria with minimum inhibitory concentrations of 6.5 mg/mL, 3.25 mg/mL, and 0.2 mg/mL forE. coliUSTCMS 1030,P. aeruginosaUSTCMS 10013 andS. aureusUSTCMS 1097, respectively. Based on disk diffusion, the methanol and aqueous extracts ofP. betleshowed promising synergistic effect with the antibiotic amoxicillin. This was confirmed by checkerboard assay wherein the aqueous extract ofP. betleshowed an additive effect to amoxicillin againstE. coliUSTCMS 1030 (FICI = 0.66), while the methanol extract ofP. betleexhibited true synergism with amoxicillin againstP. aeruginosaUSTCMS 10013 (FICI = 0.33). This synergism between the ethanol extract ofP. betleand amoxicillin was significant since the activity of amoxicillin increased by 128-fold. This combination has potential in treating diseases associated with amoxicillin-resistantP. aeruginosa.