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Carbon monoxide has shown promise as a therapeutic agent against cancers. Reactive oxygen species (ROS)-activated CO prodrugs are highly demanded for targeted cancer treatment but remain sporadic. In addition, little attention is on how the release rate affects CO's biological effects. Herein, we describe a new type of ROS-activated metal-free CO prodrug, which releases CO with tunable release rates in response to multiple ROS and exhibits very pronounced tumor suppression effects in a mouse 4t1 breast tumor model. Importantly, for the first time, we observe both and that CO release rate has a direct impact on its antiproliferative potency and a correlation between release rate and antiproliferative activity is observed. In aggregates, our results not only deliver ROS-sensitive CO prodrugs for cancer treatment but also represent a promising starting point for further in-depth studies of how CO release kinetics affect anticancer activity.