Biofuel from microalgae is one of the promising solutions on addressing climate change by its possibility of reducing the fossil fuel dependency. Till-date, the overall competitiveness of microalgae based biorefinery is the major concern due to its unique operational mechanism, especially the biological growth of microalgae that fluctuates towards the surrounding. Therefore, a novel graph-theoretic approach has been proposed to provide an optimization approach for identifying optimal process design with the consideration of three aspects that includes: economic, environmental, and reliability. The optimization is conducted using P-graph (a powerful graph-theoretic tool) which is capable to determine optimal and near-optimal solutions based on three objective functions: (i) minimizing annual operating cost, (ii) minimizing potential environmental impact, and (iii) maximizing reliability of process. The pool of feasible solutions (optimal and near-optimal) is obtained by satisfying the constraints on both greenhouse gas emissions and its respective reliability along. Thereupon, a further analysis was carried out with the aid of TOPSIS considering three of the assessment aspects to identify the optimal microalgae biorefinery configuration