Nanoparticles (NPs) are increasingly explored for targeted skin penetration, particularly for pharmaceutical and cosmetic applications. However, the complex system between NP properties, skin structure, and experimental conditions poses significant challenges in predicting their penetration depth and pathways. To what depth do NPs penetrate the skin, and which pathways do they follow? These are the questions which we tried to answer in this paper. A n in-silico human skin model based on 20 years of literature on NPs skin penetration is developed. The model incorporates 19 independent parameters, including a wide range of NP properties, skin across species, and test conditions. Using random forest analysis coupled with Kennard-Stone sorting, the model achieves a high predictive accuracy of 95%. The study identifies hair follicle diameter as the most critical factor influencing NP penetration across skin layers, surpassing other skin properties, NP properties, or experimental variables. Pig and rabbit skin are the most suitable models for simulating human skin in NP penetration studies. Additionally, the in-silico model reveals that NPs in emulsions and oil-based media predominantly follow the intercellular and transappendageal route. In contrast, those embedded in aqueous media favor the intracellular route. These findings offer insights for optimizing NP-based drug delivery systems.