Aims This study was aimed to develop Isotretinoin (ITN) and alpha-tocopherol acetate (alpha-TA) loaded solid lipid nanoparticle topical gel for better skin sensitivity and potentiation of efficacy. Methods ITN and alpha-TA-loaded solid lipid nanoparticles (AE-SLN) were prepared by microemulsion method with glyceryl mono-stearate as lipid and tween 80: butanol as surfactant(mix)and characterised. AE-SLN gel was evaluated for physicochemical characteristics, drug release, skin irritation and anti-acne activity in rats. Results AE-SLNs had mean particle size of 193.4 nm (zeta-potential -29 mV) and entrapment efficiency of 84%w/w for ITN and 77.4%w/w for alpha-TA. AE-SLN gel showed sustained drug release for 24 h with a final cumulative release of 95.8% w/w and 89.1%w/w for ITN and alpha-TA. AE-SLN gel showed no erythema or edoema in rabbits and potent efficacy in rat model of acne. Conclusion In conclusion, AE-SLN gel has the potential to use as a non-irritant topical formulation for the treatment of acne.