Background American Academy of Sleep Medicine guidelines suggest that clinical prediction algorithms can be used to screen patients with obstructive sleep apnea (OSA) without replacing polysomnography, the gold standard. Objective We aimed to identify, gather, and analyze existing machine learning approaches that are being used for disease screening in adult patients with suspected OSA. Methods We searched the MEDLINE, Scopus, and ISI Web of Knowledge databases to evaluate the validity of different machine learning techniques, with polysomnography as the gold standard outcome measure and used the Prediction Model Risk of Bias Assessment Tool (Kleijnen Systematic Reviews Ltd) to assess risk of bias and applicability of each included study. Results Our search retrieved 5479 articles, of which 63 (1.15%) articles were included. We found 23 studies performing diagnostic model development alone, 26 with added internal validation, and 14 applying the clinical prediction algorithm to an independent sample (although not all reporting the most common discrimination metrics, sensitivity or specificity). Logistic regression was applied in 35 studies, linear regression in 16, support vector machine in 9, neural networks in 8, decision trees in 6, and Bayesian networks in 4. Random forest, discriminant analysis, classification and regression tree, and nomogram were each performed in 2 studies, whereas Pearson correlation, adaptive neuro-fuzzy inference system, artificial immune recognition system, genetic algorithm, supersparse linear integer models, and k-nearest neighbors algorithm were each performed in 1 study. The best area under the receiver operating curve was 0.98 (0.96-0.99) for age, waist circumference, Epworth Somnolence Scale score, and oxygen saturation as predictors in a logistic regression. Conclusions Although high values were obtained, they still lacked external validation results in large cohorts and a standard OSA criteria definition. Trial Registration PROSPERO CRD42021221339; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=221339