In the context of geologic carbon dioxide (CO2) sequestration, the storage effectiveness of a caprock–reservoir system is a function of the properties of both the caprock and reservoir – namely, the ability of the caprock to prevent upward leakage of CO2 (caprock sealing capability), the mechanical response of the reservoir and caprock (by evaluating in situ stress changes), and the extent and degree to which CO2 can be trapped over long periods of time. In this work, all three parameters were considered to evaluate the storage effectiveness of the Cambrian–Ordovician sequence of the Northern Appalachian Basin. We constructed a series of hydro‐mechanical models to investigate interactions between CO2 flow and geomechanical processes and to evaluate the three aspects of storage performance. Models were built to evaluate two scenarios: (1) single reservoirs with a single overlying caprock, and (2) systems comprising multiple reservoirs and multiple intermediate caprock units in addition to the primary (uppermost) caprock unit. The overall conclusion of the work is that focusing only on one aspect of storage effectiveness might not necessarily warrant long‐term CO2 storage. Results of the sensitivity analysis for the single caprock–reservoir system show that each storage effectiveness metric has its own control parameters. A comparison among three stacked caprock–reservoir systems in different parts of the study area shows that each location in the study area could be appropriate for one of the storage effectiveness metrics. Therefore, we conclude that the screening process to select the best site for CO2 sequestration should be based on an evaluation of all three metrics. © 2019 Society of Chemical Industry and John Wiley & Sons, Ltd.