Selective inhibition of the CSBP/p38 mitogen-activated protein kinase pathway may be an attractive target for the development of therapeutic agents to treat chronic inflammatory disease. A series of Phenoxypyrimidine Derivatives as Potent Inhibitors of p38 Kinase was subjected to quantitative structure-activity relationship (QSAR) analysis to find the structural requirements for ligand binding. A collection of chemometrics methods including multiple linear regression (MLR), factor analysis-based multiple linear regression (FA-MLR), principal component regression and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were employed to make connections between structural parameters and enzyme inhibition. The results revealed the significant roles of steric effect, hydrogen bonding and electronic properties on the p38 inhibitory activity of the studied molecules. The most significant QSAR model, obtained by GA-PLS, could explain and predict 98% and 87% of variances in the pIC(50) data, respectively.