In this work, the synthesis of bisphenol S (4,4 '-BPS) using reactive dehydration in a rotating packed bed (RPB) was studied. Firstly, orthogonal experiments were adopted to investigate the effects of different operating conditions on the yield and content of 4,4 '-BPS in a stirred tank reactor (STR), including the mesitylene/phenol molar ratio (mu), reflux dehydration time (t), and stirring speed (n), in order to optimize the operating conditions in STR. Based on the study in STR, the effects of operating conditions, including rotation speed (N), feeding rate (q), and cycle number (tau), on the yield and content of 4,4 '-BPS in RPB combined with STR (RPB-STR) were further investigated to optimize the operating conditions. The results indicated that compared to STR, the yield and content of 4,4 '-BPS increased by 22.1% and 7.52% under the optimal operating conditions in RPB-STR, respectively. This work provides a novel route for efficient synthesizing 4,4 '-BPS.