Principal component analysis (PCA) is a common tool in the literature and widely used for process monitoring and fault detection. Traditional PCA is associated with the two well-known control charts, the Hotelling’s T2 and the squared prediction error (SPE), as monitoring statistics. This paper develops the use of new measures based on a distribution dissimilarity technique named Kullback-Leibler divergence (KLD) through PCA by measuring the difference between online estimated and offline reference density functions. For processes with PCA scores following a multivariate Gaussian distribution, KLD is computed on both principal and residual subspaces defined by PCA in a moving window to extract the local disparity information. The potentials of the proposed algorithm are afterwards demonstrated through an application on two well-known processes in chemical industries; the Tennessee Eastman process as a reference benchmark and three tank system as an experimental validation. The monitoring performance was compared to recent results from other multivariate statistical process monitoring (MSPM) techniques. The proposed method showed superior robustness and effectiveness recording the lowest average missed detection rate and false alarm rates in process fault detection.