Vitamin B6, first identified by Paul György in 1934, exists in six forms, with pyridoxal 5′-phosphate (PLP) being the active form essential for the metabolism of various amino acids. In animal experiments, B6 deficiency is correlated with inflammation, but the mechanism remains unclear. Epidemiologic studies indicate lower PLP concentrations in rheumatoid arthritis patients, with some studies demonstrating an inverse relationship between PLP levels and C-reactive protein, an inflammation marker. However, human interventional trials have not shown consistent results regarding the effectiveness of vitamin B6 in reducing inflammation. On the other hand, animal studies have consistently suggested that vitamin B6 has anti-inflammatory functions, with high doses of vitamin B6 suppressing inflammation across various models. Mechanistically, vitamin B6 is linked to NF-κB and NLR family pyrin domain-containing 3 inflammasome activation, which regulates inflammation. PLP may also influence inflammation via metabolic pathways involving kynurenic acid, homocysteine, and sphingosine-1-phosphate. Despite promising findings, further research is needed to determine the optimal vitamin B6 intake for inflammation control, especially in human studies, where inconsistencies exist. Establishing appropriate dosages and timing for supplementation will be crucial for its potential therapeutic use.