The precipitation of struvite from wastewater is a potential alternative for the recovery of nutrients, especially phosphorus, which is an essential macronutrient for agriculture but can be harmful to the environment when improperly disposed of in water bodies. In addition, struvite has elements of great added value for agricultural activity (P, N, and Mg) and is, therefore, considered a sustainable alternative fertilizer. In its formation process, several intervening physicochemical factors may be responsible for the production yield levels. Optimization processes can help to define and direct the factors that truly matter for precipitation. In this context, a sequential design of experiments (DOE) methodology was applied to select and optimize the main struvite precipitation factors in wastewater. Initially, a screening was performed with eight factors with the aid of Plackett−Burman design, and the factors with a real influence on the process were identified. Then, a Doehlert design was used for optimization by applying the response surface methodology and the desirability function. The results were used to identify the optimal points of the pH (10.2), N/P ratio (≥4), and initial phosphorus concentration (183.5 mg/L); these values had a greater effect on phosphorus recovery and the production of struvite, which was confirmed through thermochemical analysis of the decomposition of its structure by differential scanning calorimeter—glass transition temperature (DSC-TG) and phase identification by X-ray diffraction (XRD). The determination of the best synthesis conditions is an enormous contribution to the control of the process because these conditions lead to better yields and higher levels of phosphorus recovery.