Marine plants are a rich source of bioactive compounds with unique properties. The Mediterranean seagrass Posidonia oceanica is particularly abundant in phenolics and flavonoids, which exhibit antioxidant and anti-inflammatory activities. In this study, a phenolic-rich extract (POS) was obtained from beach-cast P. oceanica leaves using supercritical fluid extraction (SFE), an eco-friendly technique that preserves thermolabile compounds and avoids organic solvents. POS was incorporated into a base cream (POS-enriched cream) to evaluate its bioactive potential in topical applications. The antioxidant capacity of POS and the cream formulation was firstly evaluated using the DPPH radical scavenging assay, confirming strong radical scavenging activity for the POS (IC50 = 2.32 ± 0.33 mg/mL) and significant activity for the POS-enriched cream (IC50 = 16.76 ± 0.58 mg/mL) compared to a base cream as control (IC50 = 37.62 ± 1.27 mg/mL). The antioxidant and photoprotective effects of POS were investigated in human skin fibroblasts (HS-68) exposed to oxidative stress and UV-induced damage, while anti-melanogenic activity was assessed in human epidermal melanocytes (HEM) by measuring tyrosinase activity and melanin content. POS significantly reduced ROS accumulation and modulated key molecular pathways involved in apoptosis (p-JNK), inflammation (NF-κB), energy balance (p-AMPK), and collagen synthesis (Col1A1) in fibroblasts. In melanocytes, both POS pure extract and POS-enriched cream effectively inhibited tyrosinase activity while maintaining unaltered basal melanin levels, indicating a modulatory rather than fully suppressive effect. These findings highlight the potential of P. oceanica SFE extracts as sustainable natural marine-derived products for photoprotection and anti-melanogenesis, thereby bridging the gap between marine waste stream management and applications in skin health and anti-aging strategies.