In response to the tenets of Industry 4.0, operation optimization in industrial processes has become a significant research topic. However, the uncertainties prevailing in the process pose challenges to production operations, especially the feedstock properties. In this work, the operation optimization study is performed on a distillation unit (DU), a typical plant in the industrial process. To enhance production performance, a modeling and operation optimization strategy based on feedstock property and production features is presented. One of the difficulties is how to uncover features from high-dimensional and imperfect data, where imperfect data refers to product quality data that is unavailable online. In the strategy, we inject the inherent characteristic of the process into the data-driven method to extract the feedstock property in a data-based and knowledge-oriented manner. Further, optimal feature representation and process modeling can be achieved by customizing the network structure. The operation optimization problem is formulated to adjust the top temperature of the distillation column (TTDC) to achieve satisfactory production under varying feedstock properties. Experimental results illustrate that the process model based on feedstock property and production features (PM-FP-PF) can better fit the physical process mechanism even based on incomplete information in industrial data. Industrial experiments have shown the proposed strategy has advanced generalization ability to the different feedstock properties. The proposed operation optimization strategy (OOS) improves the product qualification rate and has broad application prospects in industrial processes with similar features. Note to Practitioners—Industrial processes suffer from a variety of disturbances that interrupt the smooth operation of the system, such as varying feedstock properties. How to deal with them is the key to improve the product qualification rate. In this work, we propose a data-dr...