Dandruff is a scalp disorder characterized by flaking skin and itch of an excessive oily scalp skin. It affects 55% of the global youth and adult population. Seborrheic dermatitis is a similar scalp skin disorder with aggravated itchy rashes and flaking. Different factors are identified in the dandruff development: increased sebum production, uncontrolled fungal growth of Malassezia strains and individual reaction to pro-inflammatory environment, and the susceptibility to trigger an immunological response. Using in vitro and ex vivo models, we show that an Epilobium angustifolium extract dose dependently reduces lipid synthesis in sebocytes to a maximum of -43% (1% extract), and protects the epidermis from Malassezia-induced morphological changes. Epilobium angustifolium extract also acts through innovative mechanisms involving regulations of defensins (human beta-defensins [hBD2] and hBD3) and toll-like receptor 2 involved in the immunological response of the skin. The anti-dandruff and sebum-regulating efficacy of E. angustifolium extract (1.5%) was confirmed in a clinical study that mobilized 24 volunteers with dandruff and greasy scalp for 30 days. At the end of the study, nonadherent and adherent dandruffs were significantly (p < 0.0001) reduced in average by -54% and -48%, respectively. Using Sebumeter® measurements, scalp sebum production was inhibited by -67% (p < 0.0001) in average over baseline. In conclusion, E. angustifolium extract offers a new innovative approach to dandruff reduction through immunomodulation of the skin response to Malassezia invasion.