This paper outlines a hybrid modeling approach to facilitate weather-based operation and energy optimization for the largest Italian wastewater treatment plant (WWTP). Two clustering methods, K-means algorithm and Gaussian mixture model (GMM) based on the expectation-maximization (EM) algorithm, were applied to an extensive dataset of historical and meteorological records. This study addresses the problem of determining the intrinsic structure of clustered data when no information other than the observed values is available. Two quantitative indexes, namely the Bayesian information criterion (BIC) and the Silhouette coefficient using Euclidean distance, as well as two general criteria, were implemented to assess the clustering quality. Furthermore, seven weather-based influent scenarios were introduced to the process simulation model, and sets of aeration strategies are proposed. The results indicate that incorporating weather-based aeration strategies in the operation of the WWTP improves plant energy efficiency.