The aim was to assess the impact of high-intensity interval training (HIIT) on patients with musculoskeletal disorders. We conducted a search of Medline, Embase, PEDro, and Google Scholar. We conducted a meta-analysis to determine the effectiveness of HIIT on pain intensity, maximal oxygen consumption (VO2 max), disability, and quality of life (QoL). We employed the GRADE and PEDro scales to rate the quality, certainty, and applicability of the evidence. Results showed significant differences in pain intensity, with a moderate clinical-effect (SMD = −0.73; 95% CI: −1.40–−0.06), and in VO2 max, with a moderate clinical-effect (SMD = 0.69; 95% CI: 0.42–0.97). However, the meta-analysis showed no statistically significant results for disability (SMD = −0.34; 95% CI: −0.92–0.24) and QoL (SMD = 0.40; 95% CI: −0.80–1.60). We compared HIIT against other exercise models for reducing pain intensity and increasing VO2 max. The meta-analysis showed no significant differences in favour of HIIT. Meta-regression analysis revealed that pain intensity scores were negatively associated with VO2 max (R2 = 82.99%, p = 0.003). There is low-moderate evidence that the HIIT intervention for patients with musculoskeletal disorders can reduce pain intensity and increase VO2 max but has no effect on disability and QoL. Results also showed that HIIT was not superior to other exercise models in reducing pain intensity and increasing VO2 max.