Background: Ultraviolet radiation (UVR) causes premature skin aging. Litchi seed (LS) is considered a natural plant extract with potential antioxidant, anti-aging and anti-inflammatory properties. However, the mechanisms of LS’s protective effects on skin photoaging remain unclear. Objective: This study aims to perform a rapid and efficient virtual screening of the main targets and possible mechanisms of the protective effect of LS on skin photoaging through network pharmacology, bioinformatics and molecular docking. Methods: The primary active compounds and their corresponding targets of LS were obtained from the TCMSP, STP, and UniProt databases. Concurrently, photoaging-related targets were mined from the GEO, GeneCards, and OMIM databases. “LS-photoaging” targets were identified using Venn diagrams created with R software. Protein-protein interaction (PPI) networks and “compound-target-disease” networks were constructed and analyzed using Cytoscape. GO and KEGG pathway enrichment analyses were then performed to predict the protective mechanisms of LS against skin photoaging. Finally, key targets and active compounds were validated through molecular docking using AutoDock Vina. Results: The screening identified 368 targets of LS active compounds and 872 photoaging-related targets. Network topology analysis revealed 87 common targets, with AKT1, IL6, TP53, and CASP3 as core targets. Enrichment analysis reveals that LS can modulate the ROS/MAPK/AP-1 pathway, thereby inhibiting inflammatory responses and reducing oxidative stress, which leads to a decrease in pro-inflammatory factors. Additionally, it promotes collagen restoration by suppressing the expression of MMPs. Molecular docking validation demonstrated a strong binding affinity between the core targets and the key compounds. Conclusion: LS shows potential for treating photoaging by counteracting inflammation and oxidative stress, regulating collagen and lipid metabolism, and inhibiting apoptosis.