The Great Oxidation Event (GOE) at 2.45 Ga facilitated the global expansion of oxidized compounds in seawater. Here, we demonstrate that the GOE coincided with a sharp increase in arsenate and arsenic sulfides in marine shales. The dramatic rise of these oxygen-sensitive tracers overlaps with the expansion of key arsenic oxidants, including oxygen, nitrate, and Mn(IV) oxides. The increase in arsenic sulfides by at least an order of magnitude after 2.45 Ga is consistent with the proposed transition to mid-depth continental-margin sulfide-rich waters following the GOE. At the same time, the strong increase in arsenate content, to similar to 60% of the total arsenic concentration in shales, suggests that the oxidative component of the arsenic cycle was established for the first time in Earth's history. These data highlight the global emergence of a new selective pressure on the survival of marine microbial communities across the GOE, the widespread appearance of toxic, oxidized chemical species such as arsenate in seawater.