Zebra mussels (Dreissena polymorpha) have continued their spread within inland lakes and rivers in North America despite diligent containment and decontamination efforts by natural resource agencies and other stakeholders. Identification of newly infested waterways by early detection surveillance programs allows for rapid response zebra mussel eradication treatments in some situations. Previous eradication treatments have occurred over a broad range of water temperatures which have influenced the efficacy of molluscicides. Natural resource managers will benefit from knowledge regarding the impacts of water temperature and exposure duration on the toxicity of molluscicides to zebra mussels. In particular, temperature specific data are needed to inform the selection of an effective molluscicide and the proper dose that will induce 100% zebra mussel mortality. We evaluated the influences of temperature and exposure duration on the toxicity of two U.S. EPA-registered (EarthTec QZ and Zequanox) and two nonregistered (niclosamide and potassium chloride) molluscicides to zebra mussels at water temperatures of 7, 12, 17, and 22 °C. Our results indicate that treatment options for the eradication of zebra mussels in waters ≤ 12 °C include 336 h or longer treatments with EarthTec QZ and KCl as well as treatments with niclosamide ≥ 24 h in duration. In waters ≥ 17 °C, multiple toxicant and exposure duration combinations are potentially effective for zebra mussel eradication. On-site or in situ zebra mussel bioassays are a useful tool for the evaluation of treatment efficacy.