The Steptoean Positive Carbon Isotope Excursion (SPICE) event at ca. 497-494 Ma was a major carbon-cycle perturbation of the late Cambrian that coincided with rapid diversity changes among trilobites. Several scenarios (e.g., climatic/oceanic cooling and seawater anoxia) have been proposed to account for an extinction of trilobites at the onset of SPICE, but the exact mechanism remains unclear. Here, we present a chemostratigraphic study of carbonate carbon and carbonate-associated sulfate sulfur isotopes (8¹³C_carb and 834S_CAS) and elemental redox proxies (U_EF, Mo_EF, and C_org/P), augmented by secular trilobite diversity data, from both upper slope (Wangcun) and lower slope (Duibian) successions from the Jiangnan Slope, South China, spanning the Drumian to lower Jiangshanian. Redox data indicate locally/regionally well-oxygenated conditions throughout the SPICE event in both study sections except for low-oxygen (hypoxic) conditions within the rising limb of the SPICE (early-middle Paibian) at Duibian. As in coeval sections globally, the reported δ¹³C_carb and δ34S_CAS profiles exhibit firstorder coupling throughout the SPICE event, reflecting co-burial of organic matter and pyrite controlled by globally integrated marine productivity, organic preservation rates, and shelf hypoxia. Increasing δ³⁴S_CAS in the “Early SPICE” interval (late Guzhangian) suggests that significant environmental change (e.g., global-oceanic hypoxia) was under way before the global carbon cycle was markedly affected. Assessment of trilobite range data within a high-resolution biostratigraphic framework for the middle-late Cambrian facilitated reevaluation of the relationship of the SPICE to contemporaneous biodiversity changes. Trilobite diversity in South China declined during the Early SPICE (corresponding to the End-Marjuman Biomere Extinction, or EMBE, of Laurentia) and at the termination of the SPICE (corresponding to the End-Steptoean Biomere Extinction, or ESBE, of Laurentia), consistent with biotic patterns from other cratons. We infer that oxygen minimum zone and/or shelf hypoxia expanded as a result of locally enhanced productivity due to intensified upwelling following climatic cooling, and that expanded hypoxia played a major role in the EMBE at the onset of SPICE. During the SPICE event, global-ocean ventilation promoted marine biotic recovery, but termination of SPICE-related cooling in the late Paibian may have reduced global-ocean circulation, triggering further redox changes that precipitated the ESBE. Major changes in both marine environmental conditions and trilobite diversity during the late Guzhangian demonstrate that the SPICE event began earlier than the Guzhangian-Paibian boundary, as previously proposed.