This study aimed to elucidate the mechanism through which luteolin/polyvinyl alcohol/sodium alginate (Lut/PVA/SA) hydrogel promotes the healing of pressure injury (PI), thereby offering optimized strategies for clinical management. Four formulations of PVA/SA hydrogel were synthesized using chemical cross-linking combined with freeze-thaw cycles. The optimal formulation was then selected based on its physicochemical properties to construct the Lut/PVA/SA drug delivery system. The characterization and biocompatibility of the materials were evaluated by CCK-8 assay, PI/Calcein-AM double staining, and Fourier transform infrared spectroscopy. A stage II PI model was established in Sprague-Dawley (SD) rats to evaluate therapeutic efficacy and histopathological changes. Network pharmacology identified potential targets of Lut, with KEGG enrichment analysis and systematic literature review predicting the underlying mechanisms. RT-qPCR, Western blotting and immunofluorescence were performed to assess anti-inflammatory, antioxidant and anti-apoptotic effects of the hydrogel. The result showed that Lut/PVA/SA hydrogel exhibited superior physicochemical properties and significantly accelerated wound healing. Treatment with the hydrogel enhanced collagen deposition and increased expression of α-SMA and Collagen I. Compared with model group, treatment with Lut/PVA/SA hydrogel activated the NRF2/HO-1 signaling pathway, upregulated the level of SOD and CAT, while downregulated the level of MDA. Additionally, in the Lut/PVA/SA hydrogel groups, the expression of pro-apoptotic proteins BAX and Caspase 3 were downregulated, the expression of anti-apoptotic protein BCL2 was upregulated, resulting in the restoration of the BAX/BCL2 ratio. The expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were significantly suppressed. In conclusion, Lut/PVA/SA hydrogel can effectively promote the healing of stage II PI in SD rats. Its therapeutic effect may be attributed to the enhanced antioxidant capacity by activating the NRF2/HO-1 pathway, regulating the BAX/BCL2 ratio to inhibit fibroblast apoptosis, further alleviating the inflammatory microenvironment. These actions collectively promote collagen synthesis to facilitate wound repair.