This study examined managing innovation and university system sustainability in Cross River State, Nigeria. The study adopted a descriptive survey research design, which was considered appropriate for systematically collecting and analyzing data from respondents to make valid generalizations about the population. The population comprised Vice Chancellors, Deputy Vice Chancellors, Directors, Deans, Heads of Departments, and Unit Heads in public universities in Cross River State, estimated at 523 respondents from the University of Calabar and the University of Cross River State. A sample size of 750 respondents was used, selected through census sampling technique, involving all relevant academic and administrative decision-makers responsible for innovation and sustainability in the universities. Data were collected using a 40-item structured questionnaire titled Managing Innovation and University System Sustainability Questionnaire (MIUSSQ). The instrument was validated by experts in Educational Management, Measurement and Evaluation, and Innovation Studies, while reliability was established using Cronbach’s Alpha, yielding a coefficient of 0.86, indicating high internal consistency. Data were analyzed using mean, standard deviation, Pearson Product Moment Correlation Coefficient, and One-way Analysis of Variance (ANOVA). Findings revealed that technological innovation, administrative innovation, research and development innovation, and organizational culture for innovation all had significant positive influences on university system sustainability in Cross River State. The study concluded that effective management of innovation significantly enhances the sustainability of university systems.