Spironolactone (SP) known as an anti-androgen drug, has been proven to be effective in treatment of acne. The quest to minimize the unnecessary systemic side effects associated with the oral drug administration of spironolactone, has led to a growing interest of loading SP on lipid nanoparticles to deliver the drug in a topical formulation. The aim of the current investigation was to prepare and compare the performance of SP loaded nanostructured lipid carrier (SP-NLC) and SP alcoholic gels (SP-ALC) on two groups of respective patient populations, group A and group B in the treatment of mild to moderate acne vulgaris. The results showed that SP-NLCs were spherical in shape with an average diameter of ~240 nm. The polydispersity index (PI) and zeta potential of these nanoparticles were 0.286 and -21.4 respectively. The gels showed non-Newtonian independent pseudoplastic and shear thinning behavior. The SP-NLCs was not toxic to fibroblast cell strains at the 24 and 48 h periods. Results showed that the mean number of total lesions (37.66 ± 9.27) and non-inflammatory lesions (29.26 ± 7.99) in group A significantly decreased to 20.31 ± 6.58 (p < 0.05) and to 13.95 ± 5.22 (p < 0.05) respectively. A similar pattern was observed for group B where the mean number of total lesions and non-inflammatory lesions reduced from 33.73 ± 9.40 to 19.13 ± 5.53 (p < 0.05) and from 25.65 ± 8.12 to 13.45 ± 4.48 (p < 0.05) respectively. The total lesion count (TLC) was significantly decreased from 37.16 ± 9.28 to 19.63 ± 6.36 (for group A; p < 0.071) and 32.60 ± 9.32 to 18.33 ± 5.55 (for group B; p < 0.05) respectively. After treatment with SP-NLC for 8 weeks, the water content of the skin significantly (p < 0.05) increased from 37.44 ± 8.85 to 45.69 ± 19.34 instrumental units. Therefore, the SP-NLC gel may help in controlling acne vulgaris with skin care benefits.