Accurate determination of the binding affinity of the ligand to the receptor remains a difficult problem in computer-aided drug design. Here, we study and compare the efficiency of Jarzynski's equality (JE) combined with steered molecular dynamics and the linear interaction energy (LIE) method by assessing the binding affinity of 23 small compounds to six receptors, including β-lactamase, thrombin, factor Xa, HIV-1 protease (HIV), myeloid cell leukemia-1, and cyclin-dependent kinase 2 proteins. It was shown that Jarzynski's nonequilibrium binding free energy ΔGneqJar correlates with the available experimental data with the correlation levels R = 0.89, 0.86, 0.83, 0.80, 0.83, and 0.81 for six data sets, while for the binding free energy ΔGLIE obtained by the LIE method, we have R = 0.73, 0.80, 0.42, 0.23, 0.85, and 0.01. Therefore, JE is recommended to be used for ranking binding affinities as it provides accurate and robust results. In contrast, LIE is not as reliable as JE, and it should be used with caution, especially when it comes to new systems.