Isometric handgrip exercise has been suggested to promote some health-related factors (e.g., lowering blood pressure). However, there is a need to evaluate whether this type of exercise can be included as an option to elicit these health-related outcomes. The purpose of the article was to systematically review the acute and chronic effects of isometric handgrip exercise on resting blood pressure, pain sensation, cognitive functionand blood lipids and lipoproteins. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 89 studies met our inclusion criteria. Most randomized controlled trials (17/26) reported reductions in resting blood pressure (mostly systolic blood pressure) following isometric handgrip training. There were inconsistent results in isometric handgrip exercise-induced hypotension (i.e., acute response). There was convincing evidence observed in randomized controlled trials (4/6) for isometric handgrip exercise-induced hypoalgesia. Some randomized controlled trials (2/2) supported an improvement in memory performance, but not interference control (0/2), after a session of isometric handgrip exercise. None of the included studies found any effects of isometric handgrip training on blood lipids and lipoproteins. Isometric handgrip exercise appears to be an effective method to improve certain health-related factors. The acute reductions in pain and blood pressure may share a similar central mechanism. However, training-induced reductions in resting blood pressure may be driven by changes in the periphery. Additional work is needed to better understand if (and to what extent) isometric handgrip exercise (or training) influences cognitive function and blood lipids and lipoproteins.