In order to assess the impact of high-intensity interval training (HIIT) on biological and body composition variables in patients with musculoskeletal disorders (MSKD), a systematic search on PubMed (Medline), CENTRAL, CINAHL, Web of Science, SPORTDiscus, and Scopus was conducted. Standardized mean differences (SMD) and 95% confidence intervals were calculated and pooled in a meta-analysis using the random-effects model. The effectiveness of HIIT on waist circumference, muscle mass, resting heart rate, resting systolic and diastolic blood pressure, C-reactive protein, body weight, and body fat were determined. GRADE, risk of bias 2, and PEDro scales were employed. HIIT compared to no intervention, minimal intervention, or usual care did not show significant results in its favor on any of the variables studied, except for the resting heart rate when compared with no intervention (SMD = −0.33; 95% CI: −0.63, −0.04; heterogeneity Q value: 0.14; p = 0.93; I2 = 0%). In addition, HIIT also does not seem to be more effective than moderate-intensity continuous training. Based on the results, it seems that HIIT has almost no significant effects on biological and body composition variables, except for resting heart rate, in patients with MSKD.