Whole-brain network analysis is commonly used to investigate the topology of the brain using a variety of neuroimaging modalities. This approach is notable for its applicability to a large number of domains, such as understanding how brain network organization relates to cognition and behavior and examining disrupted brain network organization in disease. A benefit to this approach is the ability to summarize overall brain network organization with a single metric (e.g., global efficiency). However, important local differences in network structure might exist without any corresponding observable differences in global topology, making a whole-brain analysis strategy unlikely to detect relevant local findings. Conversely, using local network metrics can identify local differences, but are not directly informative of differences in global topology. Here, we propose the network statistic (NS) jackknife framework , a simulated lesioning method that combines the utility of global network analysis strategies with the ability to detect relevant local differences in network structure. We evaluate the NS jackknife framework with a simulation study and an empirical example comparing global efficiency in children with attention-deficit/hyperactivity disorder (ADHD) and typically developing (TD) children. The NS jackknife framework has been implemented in a public, open-source R package, netjack , available at https://cran.r-project.org/package=netjack .