A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for <i>in vitro</i> toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infection. Oxadiazole <b>72c</b> shows potent <i>in vitro</i> antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.