Cyclones are the most widely used industrial dust collecting devices for removing particulate matter from air streams. In this work, a new optimization model of multiple cyclone arrangement is presented using General Algebraic Modeling System (GAMS) software in obtaining the optimal number and dimensions of the cyclone, and the best cyclone arrangement for a certain condition with respect to the minimum total cost, including the operating cost and the capital cost. The proposed model of nonlinear programming (NLP) and mixed integer nonlinear programming (MINLP) has been successfully applied to different case studies. The NLP model is applied to an NPK (Nitrogen, Phosphorus, and Potassium) fertilizer plant to find the optimal number and dimensions of the 1D3D, 2D2D, and 1D2D cyclones arranged either in parallel or series. In another case study, the best cyclone arrangement of parallel-series for three different combinations of the 1D3D and 2D2D cyclone is obtained through the use of MINLP modeling. The results show that each type of cyclone (i.e., 1D3D, 2D2D, and 1D2D) has an alternative that can be arranged either in parallel or in series configuration with different optimal numbers of cyclones. Furthermore, in the parallel-series arrangement, the cyclone of 2D2D+2D2D is found to be more economical and efficient compared to the others.