Inflammation is a critical defense mechanism that creates hostile conditions to prevent tissue infection and repair damage in humans and animals. However, when inflammation resolution is delayed or compromised, it can lead to chronic illnesses. Redox balance disturbances and oxidative stress are major factors causing over-inflammation, leading to the development of various chronic diseases. Silymarin (SM) and its main constituent, silibinin/silybin (SB), have been extensively studied for their anti-inflammatory properties. The primary anti-inflammatory mechanism of SM/SB involves inhibiting TLR4/NF-κB-mediated signaling pathways and downregulating pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, IL-12, IL-23, CCL4, and CXCL10. Additionally, SM/SB upregulates anti-inflammatory cytokines (IL-4, IL-10, IL-13, TGF-β) and lipid mediators involved in inflammation resolution. These properties have been demonstrated in various in vitro and in vivo models, including immune and non-immune cells, toxicity models, nonalcoholic fatty liver disease, ischemia/reperfusion models, stress-induced injuries, aging, exercising models, and wound healing. The anti-inflammatory activities of SM/SB are key elements in their health-promoting properties, making them valuable natural antioxidants.Inflammation is a critical defense mechanism that creates hostile conditions to prevent tissue infection and repair damage in humans and animals. However, when inflammation resolution is delayed or compromised, it can lead to chronic illnesses. Redox balance disturbances and oxidative stress are major factors causing over-inflammation, leading to the development of various chronic diseases. Silymarin (SM) and its main constituent, silibinin/silybin (SB), have been extensively studied for their anti-inflammatory properties. The primary anti-inflammatory mechanism of SM/SB involves inhibiting TLR4/NF-κB-mediated signaling pathways and downregulating pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, IL-12, IL-23, CCL4, and CXCL10. Additionally, SM/SB upregulates anti-inflammatory cytokines (IL-4, IL-10, IL-13, TGF-β) and lipid mediators involved in inflammation resolution. These properties have been demonstrated in various in vitro and in vivo models, including immune and non-immune cells, toxicity models, nonalcoholic fatty liver disease, ischemia/reperfusion models, stress-induced injuries, aging, exercising models, and wound healing. The anti-inflammatory activities of SM/SB are key elements in their health-promoting properties, making them valuable natural antioxidants.