Recent studies have shown that rutin (Quercetin‐3‐O‐rhamnosylglucoside) may have an inhibitory effect on COVID‐19. Rutin can be extracted from Tartary buckwheat as an active pharmaceutical ingredient. Nevertheless, its purification is mainly hindered by Kaempferol‐3‐O‐rutinoside (K3R) due to their similar molecular structures. This study intends to propose a simulated moving bed (SMB) chromatography process of rutin and K3R to achieve continuous production. True moving bed (TMB) and SMB models were established to numerically analyze and optimize this process. The system consists of a four‐zone SMB with two columns in each zone. The effects of the switch interval, feed flowrate, desorbent flowrate, extract flowrate, raffinate flowrate, and recycle flowrate on the purity and yield of rutin and K3R were investigated and the optimized conditions were chosen as 5 min, 3.5, 40, 34, 9.5, and 24.5 L/min, respectively. Consequently, the purities of 99.64% and 99.25%, and the yields of 99.81% and 99.37% for rutin and K3R were obtained, respectively. The simulation results can provide a guidance for the future industrial application of SF‐SMB to separate rutin and K3R.