Over time, the performance of processes may deviate from the initial design due to process variations and uncertainties, making it necessary to develop systematic methods for online optimality assessment based on routine operating process data. Some processes have multiple operating modes caused by the set point change of the critical process variables to achieve different product specifications. On the other hand, the operating region in each operating mode can alter, due to uncertainties. In this paper, we will establish an optimality assessment framework for processes that typically have multi-mode, multi-region operations, as well as transitions between different modes. The kernel density approach for mode detection is adopted and improved for operating mode detection. For online mode detection, the model-based clustering discriminant analysis (MclustDA) approach is incorporated with some a priori knowledge of the system. In addition, multi-modal behavior of steady-state modes is tackled utilizing the mixture probabilistic principal component regression (MPPCR) method, and dynamic principal component regression (DPCR) is used to investigate transitions between different modes. Moreover, a probabilistic causality detection method based on the sequential forward floating search (SFFS) method is introduced for diagnosing poor or non-optimum behavior. Finally, the proposed method is tested on the Tennessee Eastman (TE) benchmark simulation process in order to evaluate its performance.