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Background: Transient receptor potential vanilloid 1 (TRPV1) is associated with skin sensitivity and mainly activated by capsaicin and heat. Interestingly, troxerutin can inhibit TRPV1 activation. However, its efficacy in reducing skin sensitivity remains undetermined. Aims: We evaluated the efficacy of troxerutin in alleviating skin sensitivity using clinical tests and in vitro experiments. Methods: For the in vitro experiment, HaCaT keratinocytes were pretreated with different concentrations of troxerutin, followed by incubation with 50 μM capsaicin for 1, 24, or 48 h. The gene and protein expressions of four inflammatory cytokines involved in skin irritation were determined. Among 35 Korean women with sensitive skin recruited for the clinical trial, 13 were involved in assessing the immediate soothing effects of 0.1% and 0.0095% troxerutin following capsaicin irritation, whereas 22 participated in evaluating the preventive soothing effect of 10% and 1% troxerutin over 4 weeks against capsaicin‐ and heat‐induced irritation. We evaluated the soothing rate using skin redness, visual analog scale, and high temperature sensitive index as evaluation indices. Results: Troxerutin inhibited the mRNA and protein expressions of cytokines in capsaicin‐treated keratinocytes. In the clinical study, 0.1% and 0.0095% troxerutin promptly alleviated capsaicin‐induced skin redness, whereas 10% troxerutin notably decreased both the visual analog scale and high temperature sensitive index for capsaicin‐ and heat‐related irritation. However, 1% troxerutin was only effective in reducing the visual analog scale in response to capsaicin irritation. Conclusions: Troxerutin can inhibit TRPV1 activation in clinical and in vitro tests. [ABSTRACT FROM AUTHOR]