Salmonella is a widespread foodborne pathogen that can exhibit multidrug resistance (MDR; resistance to ≥3 antimicrobial classes). Therefore, the development of new preventative measures against MDR Salmonella is highly important. Bacterial antibiotic resistance is commonly mediated by efflux pumps. In this study, two compounds that block efflux pump activity, 1-(1-Naphthylmethyl)-Piperazine (NMP) and Phenylalanine-arginine β-naphthylamide (PaβN), were tested with the antibiotic tetracycline to determine if a synergistic reduction in resistance could be achieved in tetracycline-resistant Salmonella. The efflux pump inhibitors (EPIs) reduced Salmonella resistance to tetracycline by 16 to 32-fold in several tetracycline resistant isolates. For example, the tetracycline minimum inhibitory concentration (MIC) for MDR Salmonella enterica serovar I 4,[5],12:i:- USDA15WA-1 (SX 238) was 256 μg/mL. However, in the presence of NMP (250 μg/mL), the MIC dropped to 8 μg/mL which is below the Clinical Laboratory Standards Institute (CLSI) breakpoint for tetracycline resistance in Salmonella (≥16 μg/mL). Confocal and transmission electron microscopy revealed NMP-mediated damage to Salmonella membranes at a higher concentration (1000 μg/mL), implying that the EPI disrupts membrane morphology which can lead to cell death; however, this effect was dependent on NMP concentration, as NMP blocked efflux activity with less of a membrane-disrupting effect at a lower concentration (250 μg/mL). These findings suggest that the use of EPIs can reduce the MIC of tetracycline and restore the effectiveness of the antibiotic against tetracycline-resistant Salmonella.