This investigation correlates effective leadership with organizational performance of public universities in Ecuador, while employee well-being plays a mediating role. Such a topic is relevant because public educational management must be maximized since many public entities struggle with resources and human talent—such challenges translate to critical determinants of institutional quality and public and private market competitiveness. Moreover, whilst literature exists on leadership and performance, few have explored the mediation role of employee well-being in Latin America; thus, an opportunity arises to fill the literature gap with meaningful findings. Thus, to solve the problem, an approach based on neutrosophic plithogenic hypotheses occurred alongside structural equation modeling and researcher-validated questionnaires to assess 285 professors at four public universities. The findings indicate effective leadership positively influences organizational performance while employee well-being significantly mediates the relationship between the two variables; 54.3% of the organizational performance variance is attributed to employee well-being. Therefore, this work contributes to the field by finding empirical validation of a relational model between three variables while accounting for uncertainty via neutrosophics—all of which creates a unique deviation from effective leadership theory. In addition, it helps educational leaders practically by allowing the creation of policies based on teacher input for teacher well-being and subsequently, effective and higher-performing public universities.