Deep Water Running (DWR) is a form of aquatic aerobic exercise simulating the running patterns adopted on dry land. Little is known on the effectiveness of DWR despite gaining popularity. The objective of this study is to systematically review the effects of DWR on cardiorespiratory fitness, physical function, and quality of life in healthy and clinical populations. A systematic search was completed using six databases, including SPORTDiscus, MEDLINE, CINAHL, AMED, Embase, and The Cochrane Library, up to February 2022. Eleven studies evaluating the effectiveness of DWR on cardiorespiratory fitness (CRF), physical function, or quality of life (QoL), compared with no interventions (or standard treatment) or land-based trainings were identified. Data relevant to the review questions were extracted by two independent reviewers when means and standard deviations were reported, and standardized mean differences were calculated. A quality assessment was conducted using selected items from the Downs and Black checklist. A total of 11 clinical trials (7 randomized controlled trials) with a total of 287 participants were included. Meta-analyses were not completed due to the high level of clinical and statistical heterogeneity between studies. Compared with land-based training, DWR showed similar effects on CRF with limited studies reporting outcomes of physical function and QoL compared with the no-exercise control group. DWR appears to be comparable to land-based training for improving CRF. The aquatic environment may provide some advantages for off-loaded exercise at high intensity in populations that are weak, injured or in pain, but more studies are required.