Topically applied all-trans-retinoic acid (RA) is a gold-standard anti-aging molecule used in dermatology. As its cosmetic counterpart used in anti-aging, Retinol (ROL) is also a known metabolic precursor of RA. Despite this metabolic link, they haven’t been compared exhaustively in vivo at a mechanistic level. Therefore, to highlight the effect of a topical application of both molecules on in vivo skin, we undertook a longitudinal 1-year study and performed an untargeted proteomic analysis to get a more holistic view on the underlying biological mechanisms of action. The generation of the temporal proteomics signatures of retinol and all-trans-retinoic acid reveals the impact of these molecules on biological functions related to the aging of skin. New biological functions impacted by retinoids were discovered: glycan metabolism and protein biosynthesis. In addition, the temporal analysis reveals highest modulations at early time points while the physical measures, such as epidermal thickening, was mostly observed at the latest time point, demonstrating a strong time lapse between molecular and morphological impacts. Finally, these global temporal signatures could be used to identify new cosmetic compounds of interest.