<p>Nitrogen-based heterocycles represent 60% of small-molecule-approved drugs. Increasing demand for sp³-rich <i>N</i>-heterocyclic scaffolds as a bioisosteric replacement in drug discovery platforms has continued to drive the development of elegant methods for the synthesis of these important molecules. Among various <i>N</i>-heterocycles, azetidine has emerged as a valuable scaffold. Aza-azetidines, indole-azetidines, and spirocyclic azetidines with tertiary or quaternary C3-carbon make structural and/or functional parts of various important drug molecules. However, an efficient and catalytic synthetic strategy to access those important scaffolds is still missing in the literature. Herein, we report HFIP-assisted Brønsted acid-catalyzed strain-release driven ring opening of 1-azabicyclo[1.1.0]butane (ABB) to access aza-azetidines, indole-azetidines, and spirocyclic azetidines with quaternary C3-carbon in good yield. Detailed experimental and theoretical studies using DFT shed light on the reaction mechanism. We also find promising antibacterial activity in one of these indole-azetidine compounds against <i>Staphylococcus</i> <i>aureus</i> MTCC 1430.</p>