In the present study, a series of 20 indane‐based 1,5‐benzothiazepines (5a–t) has been prepared derived from 3‐phenyl‐2,3‐dihydro‐1H‐inden‐1‐one (1). All the synthesized 1,5‐benzothiazepines (5a–t) were screened for their in vitro antimicrobial activities against four bacteria [Bacillus subtilis (MTCC 441), Staphylococcus epidermidis (MTCC 6880), Escherichia coli (MTCC 1652), and Pseudomonas aeruginosa (MTCC 424)] and two fungi [Candida albicans (MTCC 227) and Aspergillus niger (MTCC 8189)]. Among all the tested derivatives, 5n and 5o against E. coli displayed more inhibitory activity than that of the reference drug, ciprofloxacin, while the derivatives 5c, 5m–o, 5s, and 5t against C. albicans, and 5d, 5e, 5n, 5o, 5s, and 5t against A. niger were found to be more potent than the standard drug, that is, fluconazole.