Diclofenac (DCF) is often detected in diverse aquatic bodies, and ineffective management can lead to detrimental effects on human health and ecosystems. In this study, degradation of DCF by Fe(III) and Mn(II) activating bisulfite (BS) was investigated. In the Fe(III)/Mn(II)/BS system, 93.4% DCF was degraded at 200 μM BS within 120 s, and additional research on 1000 μM BS achieved 88.4% degradation efficacy. Moreover, kinetics fitting of DCF degradation with the different BS concentrations was studied to find the two highest reaction rates (200 and 1000 μM, kobs = 0.0297 and 0.0317 s−1, respectively). Whereafter, SO4•− and Mn(III) were identified as the main active species at these two concentrations, respectively. Density functional theory (DFT) calculations, molecular frontier orbital theory, and surface electrostatic potential (ESP) forecast electrophilic attack sites. DCF degradation pathways by radical and non-radical ways were proposed by attack site prediction and thirteen intermediates identified by UPLC-QTOF-MS. ECOSAR software 2.2 was used for toxicity assessment. This work studied DCF degradation by the Fe(III)/Mn(II)/BS process in the presence of different concentrations of BS, providing a new insight into water purification.