MRSA skin infection remains a serious health concern. Clindamycin, an FDA-approved lincosamide antibiotic, treats MRSA but is limited topically by the stratum corneum (SC) as a skin barrier. This study developed nanostructured lipid carrier (NLC) to improve clindamycin’s efficacy against MRSA wound infections. NLC was prepared using a cold microemulsion technique, optimized, and characterized for its physicochemical properties, with safety confirmed by an MTT assay in HaCat cells. Cinnamaldehyde was selected as the NLC’s oily phase due to its antibacterial properties, providing synergistic effects. The clindamycin-loaded cinnamaldehyde-based NLC exhibited a nanometric size of 100.3 ± 3.8 nm, a narrow size distribution (PDI 0.19 ± 0.0002), and a spherical morphology. In vitro antimicrobial activity was assessed on MRSA strains using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), biofilm inhibition, and regrowth bioassays. The loaded NLC enhanced antimicrobial activity against MRSA, showing 2- to 8-fold improvement over free clindamycin and unloaded blank NLC. MIC/MBC values were 1/4 μg/mL for the loaded NLC, 2/8 μg/mL for free clindamycin, and 8/64 μg/mL for blank NLC. At half the MIC concentration, the NLC inhibited MRSA biofilm formation by 67.58%, compared to 48.47% for free clindamycin. Skin permeation through SC was evaluated using Franz cells and showed improved drug permeation of the NLC formulation compared to the free drug. In vivo studies used Albino Wistar rats divided into five groups: uninfected, infected, untreated, infected treated with a marketed drug, infected treated with an unloaded formulation, and infected treated with a loaded NLC. After 7 days, agar cultures showed extensive bacterial growth in untreated rats, minimal growth in rats treated with unloaded formulation, and no growth in the loaded NLC group. Wound diameter measurements confirmed improved healing with the NLC, as analyzed using SPSS version 25. This formulation is a promising antibacterial vehicle against MRSA infections.