Biosensors are the analytical tools with great application in healthcare, food quality control, and environmental monitoring. They are of considerable interest to be designed by using cost-effective and high efficient approaches. Designing biosensors with improved functionality or application in new target detection has been converted to a fast-growing field of biomedicine and biotechnology branches. Experimental efforts have led to valuable successes in biosensor designing; however, some deficiencies limit their utilization for this purpose. Computational design of biosensors has been introduced as a promising key to eliminate the gap. A set of reliable structure prediction of the biosensor segments, their stability, and accurate descriptors of molecular interactions are required to computationally design of biosensors. In this review, we provide a comprehensive insight into the progress of computational methods to guide the biosensor design, including molecular dynamics (MD) simulation, quantum mechanics (QM) calculations, molecular docking, virtual screening, and a combination of them as the hybrid methodologies. With relying on the recent advances in computational methods, an opportunity has been emerged for them to be complementary or alternative to the experimental methods in the field of biosensor design.