Isolation valve closures (IVCs) can effectively assist pipe maintenance and management in water distribution systems (WDSs), but they inevitably cause secondary impacts on the WDS’s performance. Previous studies have mainly focused on how to optimally operate or locate valves, but few efforts have been made on investigating the secondary impacts induced by IVCs. To this end, six quantitative metrics are proposed to comprehensively evaluate physical, hydraulic, and water quality impacts caused by IVCs. These metrics are used to explore how different network topologies, valve closing strategies, and valve placement strategies affect an IVC’s overall impact on WDS performance. Applications to three real WDSs show the following: (1) the proposed metrics can effectively reveal underlying impacts caused by IVCs, especially the associated water quality risk that has rarely been considered before; (2) in addition to their surrounding pipes, IVCs can affect the water quality in pipes that are far away from the isolated segments; (3) a highly looped WDS is more likely to have higher water quality risk (e.g., due to flow direction reversal) but a lower hydraulic influence level (e.g., low pressure) compared to a WDS with many branched structures; and (4) while closing valves near the failed pipe is an overall strategy to reduce hydraulic impacts, it may also produce high water quality risk. The proposed metrics and the assessment framework are practically meaningful as they offer not only an improved understanding of the secondary impacts caused by IVCs, but also guidance for the decision-making process regarding valve maintenance and management.