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Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) continues to be one of the main causes of hospital-acquired infections in all regions of the world, while linezolid is one of the only commercially available oral antibiotics available against this dangerous gram-positive pathogen. In this study, the antibacterial activity from 32 analogues of synthetic gamma-lactam heterocycles against MRSA was determined. Amongst screened analogues for the minimum inhibitory concentration (MIC) assay, compound <b>MFM514</b> displayed good inhibitory activity with MIC values of 7.8–15.6 µg/mL against 30 MRSA and 12 methicillin-sensitive <i>S. aureus</i> (MSSA) clinical isolates, while cytotoxicity evaluations displayed a mean inhibitory concentration (IC₅₀) value of > 625 µg/mL, displaying a potential to becoming as a lead compound. In subsequent animal studies for <b>MFM514</b>, a single-dose oral acute toxicity test revealed an estimated mean lethal dose (LD₅₀) value of <5000 mg/kg, while in the mice infection test, a mean effective dose (ED₅₀) value of 29.39 mg/kg was obtained via oral administration. These results suggest that gamma-lactam carbon skeleton, particularly <b>MFM514</b>, is highly recommended to be evaluated further as a new safe and efficacious orally delivered antibacterial agent against MRSA.