The present study aimed to formulate and evaluate Clindamycin hydrochloride-loaded proniosomal gel for topical drug delivery with improved entrapment efficiency, controlled release, antimicrobial activity, and skin tolerability. The formulations were evaluated for preformulation properties, drug–excipient compatibility, entrapment efficiency, particle size, zeta potential, SEM, physicochemical properties, in-vitro drug release, release kinetics, antimicrobial activity, skin irritation, and stability. UV spectrophotometric analysis showed maximum absorption at 210 nm, with good linearity over 2–10 µg/ml (R² = 0.9992). FTIR studies indicated no significant incompatibility between Clindamycin hydrochloride and the selected excipients (Span 60, cholesterol, and soya lecithin). Among the prepared formulations, F6 was selected as the optimized formulation. It exhibited an entrapment efficiency of 86.7 ± 0.3%, particle size of 249.69 nm, PDI of 0.362, and zeta potential of 35.7 mV. SEM revealed discrete, approximately spherical vesicles. The optimized gel showed a pH of 6.45 ± 0.03, spreadability of 28.9 ± 0.05 g·cm/sec, viscosity of 8890 cps, and drug content of 85.7 ± 0.3%. In-vitro drug release reached 86.34% at 7 hours, following first-order kinetics (R² = 0.9901). The formulation demonstrated antimicrobial activity and caused no visible erythema or edema. Additionally, only minor changes in entrapment efficiency were observed during the four-week stability study. Overall, F6 demonstrated promising physicochemical properties, controlled drug release, antimicrobial activity, and topical tolerability.