Ethnopharmacological relevance: Xanthium strumarium L has long been used in traditional Chinese medicine and has shown anti-inflammatory potential in modern pharmacological studies. However, whether its aqueous extract can ameliorate psoriasis-like skin inflammation, and which fractions contribute to this activity, remain unclear. Aim of the study: This study aimed to determine whether the aqueous extract of Xanthium sibiricum ameliorates imiquimod-induced psoriasis-like skin inflammation, to identify the major active fractions through activity-guided fractionation, and to characterize their associated chemical profiles and molecular pathway features. Materials and methods: An imiquimod (IMQ)-induced psoriasis-like mouse model was used to assess the effects of X. sibiricum aqueous extract and its fractions. The aqueous extract was separated by LH-20 gel column chromatography into five fractions, designated XA1–XA5. Zebrafish survival and tail amputation-induced neutrophil recruitment assays were used for safety assessment and activity-guided screening. The active fractions were further evaluated in IMQ-treated mice using PASI-like scoring, histological analysis, Ki67 staining, immune cell infiltration analysis, cytokine detection, proteomic and transcriptomic analyses, liquid chromatography–tandem mass spectrometry (LC–MS/MS), and western blotting. Results: The aqueous extract alleviated IMQ-induced psoriasis-like skin lesions, as shown by reduced erythema, scaling, epidermal thickening, Ki67-positive cells, and inflammatory infiltration. In zebrafish, XA2, XA4, and XA5 showed stronger inhibition of neutrophil recruitment, whereas subsequent mouse experiments identified XA4 and XA5 as the main active fractions. Both fractions improved skin lesions, reduced epidermal hyperplasia, suppressed keratinocyte proliferation, and decreased inflammatory infiltration. XA4 markedly reduced IL-17, IL-23, IL-6, IL-1β, and TNF-α levels, whereas XA5 also suppressed these inflammatory mediators. Multi-omics analyses indicated distinct pathway features: XA4 was mainly associated with IL-17-related inflammatory regulation, while XA5 was linked to AMPK–mTOR-related protein changes and reduced epidermal proliferation. LC–MS/MS revealed different chemical profiles among XA2, XA4, and XA5, including caffeoylquinic acid derivatives and sesquiterpenoids. Conclusions: X. sibiricum aqueous extract exerted anti-psoriatic effects in IMQ-induced psoriasis-like skin lesions, with XA4 and XA5 identified as major active fractions. XA4 was preferentially associated with suppression of IL-17-related inflammation, whereas XA5 was more closely linked to AMPK–mTOR-related protein changes and epidermal proliferation control. These findings provide experimental evidence supporting the anti-psoriatic potential of X. sibiricum and advance the understanding of its active fraction-level pharmacological basis.