The neuropeptide relaxin-3/RXFP3 system is involved in many important physiological processes such as stress responses, appetite control, and motivation for reward. To date, pharmacological studies of RXFP3 have been limited to peptide ligands. In this study, we report the discovery of the first small-molecule antagonists of RXFP3 through a high-throughput screening campaign. Focused structure-activity relationship studies of the hit compound resulted in RLX-33 (33) that was able to inhibit relaxin-3 activity in a battery of functional assays. RLX-33 is selective for RXFP3 over RXFP1 and RXFP4, two related members in the relaxin/insulin superfamily, and has favorable pharmacokinetic properties for behavioral assessment. When administered to rats intraperitoneally, RLX-33 blocked food intake induced by the RXFP3-selective agonist R3/I5. Collectively, our findings demonstrated that RLX-33 represents a promising antagonist scaffold for the development of drugs targeting the relaxin-3/RXFP3 system.