Isotretinoin (ITR) is a drug of choice in the treatment of all types of acne, including recalcitrant, severe and nodulocystic. The most widely employed route of its administration, i.e., oral intake, is reported to be associated with severe side-effects including teratogenecity, skin dryness and psychological disorders. Topical delivery, though advised for ITR, is marked with several hiccups like irritation, erythema and peeling of skin. The current studies, therefore, were embarked upon to develop "optimized" SLNs of ITR employing formulation by design (FbD) approach. The developed system was characterized and evaluated for skin compliance, skin transport characteristics and anti-acne potential against testosterone-induced acne in male Laca mice. The SLNs were able to transport the drug to various skin layers effectively while formed drug micro-reservoirs. The nano-colloidal systems showed marked anti-acne potential and tolerability on the mouse skin vis-à-vis the marketed product. The optimized SLNs exhibited drug entrapment of 89.49±4.1%, while the size was found to be in the nano-range (i.e., 75.3±2.4 nm). The ITR formulation was found to be stable too as per ICH guidelines. The results vouch immense promise of the optimized SLNs of ITR in reducing dermal irritation and increasing the therapeutic performance, thus resulting in an efficacious and patient-compliant formulation.