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Fungal metabolites serve as a prolific source of structurally diverse bioactive compounds with significant potential for skin health and pigmentation regulation. In this study, two diastereomers of 11-hydroxycurvularin (compounds 1 and 2) and curvularin (compound 3) were isolated from Curvularia intermedia and evaluated for their anti-melanogenic and immunomodulatory effects. The diastereomeric mixture of 11-hydroxycurvularins (HC mix) exhibited superior anti-melanogenic activity in α-MSH-stimulated B16F10 melanoma cells, surpassing the efficacy of the individual diastereomers, the parent compound 3, and the positive control arbutin, without inducing cytotoxicity. Mechanistically, the HC mix exerted dual regulatory effects by inhibiting tyrosinase enzymatic activity and downregulating the transcription of core melanogenic genes (Tyr, Tyrp1, and Tyrp2). Furthermore, the HC mix attenuated LPS-induced reactive oxygen species (ROS) production and selectively regulated inflammatory gene expression in RAW 264.7 macrophages and primary murine splenocytes, downregulating IL-1β and IL-6 while upregulating TGF-β. These findings highlight that hydroxyl substitution at C-11 is critical for enhancing biological potency. Collectively, the HC mix represents a potential candidate for managing pigmentary and inflammatory skin disorders, warranting further validation in human models.