This study aimed to investigate the mechanism of active components in Shaofu Zhuyu Decoction (SZD) alleviating primary dysmenorrhea (PD) based on network pharmacology and experimental validation. A multi-database strategy was applied to identify active components of SZD and their potential targets, which were intersected with PD-related targets. Component–target and protein–protein interaction networks were constructed to screen core targets, followed by GO and KEGG enrichment analyses to elucidate key pathways. Molecular docking was further performed to validate the interactions between major components and candidate targets. An in vitro inflammatory model was established using lipopolysaccharide (LPS)-induced human uterine smooth muscle cells, and the mRNA expression levels of interleukin-6 (IL-6), tumor necrosis factor (TNF), and matrix metalloproteinase-9 (MMP9), as well as the protein expression of phosphorylated nuclear factor-κB p65(p-NF-κB p65) and calcium/calmodulin-dependent protein kinase II (CaMKII), were measured to verify the anti-inflammatory effects of SZD. A total of 197 active components and 597 potential targets were identified, among which 37 overlapping targets were associated with PD. Network analysis highlighted quercetin, kaempferol, paeoniflorin, and baicalein as key components, while TNF, IL-6, MMP9, estrogen receptor alpha (ESR1), and prostaglandin-endoperoxide synthase 2(PTGS2) were identified as core targets. GO enrichment analysis revealed significant involvement in cytokine activity, steroid hormone response, and immune regulation. KEGG pathway analysis indicated that the IL-17, TNF, and estrogen signaling pathways were major pathways implicated in the therapeutic effects of SZD, with IL-6, TNF, and MMP9 identified as key targets within the IL-17A signaling pathway. Molecular docking demonstrated favorable binding affinities between key components and targets, with binding energies below −5.0 kcal/mol. Experimental validation showed that LPS stimulation significantly increased the mRNA expression of IL-6, TNF, and MMP9, as well as the protein levels of p-NF-κB p65 and CaMKII (P<0.05), confirming successful model establishment. SZD treatment significantly reduced IL-6 and TNF expression and suppressed p-NF-κB p65 activation (P<0.05), while no significant effects were observed on MMP9 or CaMKII expression (P>0.05). In conclusion, SZD may exert therapeutic effects against PD through the synergistic actions of multiple active components by targeting key inflammatory mediators such as IL-6 and TNF within the IL-17A signaling pathway, thereby suppressing inflammatory responses and improving the uterine inflammatory microenvironment.