Recent findings have shown that Farnesoid X Receptor (FXR) antagonists might be useful in the treatment of cholestasis and related metabolic disorders. In this paper, we report the discovery of a new chemotype of FXR antagonists featured by a 3,5-disubstituted oxadiazole core. In total, 35 new derivatives were designed and synthesized, and notably, compounds <b>3f</b> and <b>13</b>, containing a piperidine ring, displayed the best antagonistic activity against FXR with promising cellular potency (IC<sub>50</sub> = 0.58 ± 0.27 and 0.127 ± 0.02 μM, respectively). The excellent pharmacokinetic properties make compound <b>3f</b> the most promising lead identified in this study.