Phenolics present in grapes have been explored as cosmeceutical principles, due to their antioxidant activity and ability to inhibit enzymes relevant for skin ageing. The winemaking process generates large amounts of waste, and the recovery of bioactive compounds from residues and their further incorporation in cosmetics represents a promising market opportunity for wine producers and may contribute to a sustainable development of the sector. The extracts obtained from grape marc and wine lees, using solid–liquid (SL) extractionwith andwithoutmicrowave (MW) pretreatment of the raw material, were characterized in terms of antioxidant activity through chemical (ORAC/HOSC/HORAC) and cell-based (keratinocytes—HaCaT; fibroblasts—HFF) assays. Furthermore, their inhibitory capacity towards specific enzymes involvedin skin ageing (elastase;MMP-1; tyrosinase)was evaluated. The total phenolic and anthocyanin contents were determined by colorimetric assays, and HPLC–DAD–MS/MS was performed to identify the main compounds. The MW pretreatment prior to conventional SL extraction led to overall better outcomes. The red wine lees extracts presented the highest phenolic content (3 to 6-fold higher than grape marc extracts) and exhibited the highest antioxidant capacity, being also the most effective inhibitors of elastase, MMP-1 and tyrosinase. The results support that winemaking waste streams are valuable sources of natural ingredients with the potential for cosmeceutical applications.