Using polygeneration systems is one of the most cost-effective ways for energy efficiency improvement, which secures a sustainable energy development and reduces environmental impacts. This paper investigates a polygeneration system powered by low to medium-grade waste heat and using CO2 as a working fluid to simultaneously produce electric power, as well as refrigeration and heating capacities. The system is simulated in Aspen HYSYS® and evaluated by applying advanced exergy-based methods. With the split of exergy destruction and investment cost into avoidable and unavoidable parts, the avoidable part reveals the real improvement potential and priority of each component. Subsequently, an exergoeconomic graphical optimization is implemented at the component level for further improving the system performance. Optimization results and an engineering solution considering technical limitations are proposed. Compared to the base case, the system exergetic efficiency was improved by 15.4% and the average product cost was reduced by 7.1%; while the engineering solution shows an increase of 11.3% in system exergetic efficiency and a decline of 8.5% in the average product cost.