Abstract: Objective: Based on multiple classical animal models, the anti-inflammatory and immunomodulatory effects of Ganoderma lucidum propolis capsules were systematically validated. Combined with network pharmacology, their mechanisms of action were explored, providing a basis for developing their medicinal and dietary dual-purpose value. Methods: In animal experiments, the anti-inflammatory effects were comprehensively evaluated using models induced by xylene-induced ear swelling in mice, acetic acid-induced increased capillary permeability in the peritoneal cavity, fresh egg white-induced paw swelling in rats, and cotton ball-induced granuloma hyperplasia. Using cyclophosphamide-induced immunodeficient mouse models, its effects on immune organ indices, pathological changes, and serum IL-4, IFN-γ, and TNF-α levels were assessed. Finally, network pharmacology was employed to screen active components and potential targets of Ganoderma lucidum and propolis, with molecular docking used to validate the binding activity between components and targets. Results: Animal studies demonstrated that Ganoderma lucidum-propolis capsules exhibited significant anti-inflammatory activity across multiple models. They inhibited xylene-induced mouse ear swelling by over 35% (P<0.01) and markedly suppressed acetic acid-induced increased capillary permeability in the peritoneal cavity, with absorbance inhibition exceeding 35% (P<0.01). In the rat paw swelling model induced by fresh egg white, the high-dose group of Ganoderma lucidum propolis capsules exhibited significant inhibitory effects at all observation time points, with the highest inhibition rate exceeding 50%; Furthermore, in the cotton ball-induced granuloma hyperplasia model, the capsules reduced the wet weight and dry weight of granulomas by approximately 25% and 30%, respectively (P<0.05), exhibiting a dose-dependent effect. In an immunosuppressed mouse model, both low- and high-dose groups of Ganoderma lucidum propolis capsules improved thymus atrophy (P<0.05, P<0.01) and alleviated splenic tissue disorganization; while the medium- and high-dose groups significantly elevated serum IL-4 and IFN-γ levels (P<0.01) and markedly reduced TNF-α levels (P<0.05). Network pharmacology screening identified 130 active components from Ganoderma and propolis, sharing 303 common targets with anti-inflammatory immunity pathways. PPI analysis indicated key targets including IL6, TNF, and AKT1. GO and KEGG analyses further suggested Ganoderma-propolis may exert effects by regulating MAPK, NF-κB, and AGE-RAGE signaling pathways. Molecular docking results demonstrated stable binding between core components and key targets, with ergosterol exhibiting a binding energy of −11.7 kcal/mol to the IL6 receptor. Conclusion: This study, through multi-model validation and network pharmacology, demonstrates that Ganoderma lucidum and propolis capsules possess significant anti-inflammatory and immune-enhancing effects, providing experimental evidence for their development as food-medicine dual-use products.