To evaluate the effect of combined systemic administration of paracetamol 500mg/codeine phosphate 30mg (PACO) and postoperative topical application of a bioactive desensitizer on in-office bleaching sensitivity and tooth color change. A randomized, triple-blind, split-mouth clinical trial was conducted. Forty volunteers ingested PACO (n = 20) or placebo (PLA) (n = 20). Their left/right hemiarches received topical application of a bioactive desensitizer [Nano-P™(NP)] and prophylactic paste (PAS), generating four treatment approaches: PACO/NP, PACO/PAS, PLA/NP, and PLA/PAS. Two bleaching sessions (35% hydrogen peroxide) were performed, and the PAS/NP were applied after the procedure. Sensitivity was obtained since the first bleaching session up to 7days post-bleaching. The color change was evaluated using CIEDE2000 and whiteness index parameters up to 7days post-bleaching. Data were analyzed using one- and two-way ANOVA/Tukey post hoc tests (p < 0.05). The PLA/PAS showed a sensitivity average of at least two times higher than the PACO/NP. The treatment approaches promoted statistically similar bleaching patterns (p > 0.05). The combined approach of systemic administration of PACO and postoperative topical application of NP reduced the level of in-office bleaching sensitivity without jeopardizing hydrogen peroxide efficacy. Professionals can adopt the combined approach of systemic administration of analgesic/anti-inflammatory drugs and topical application of a bioactive desensitizer for decreased bleaching sensitivity caused by 35% hydrogen peroxide in-office.