The resect-and-discard strategy allows endoscopists to replace post-polypectomy pathology with real-time prediction of polyp histology during colonoscopy (optical diagnosis). We aimed to investigate the benefits and harms of implementing computer-aided diagnosis (CADx) for polyp pathology into the resect-and-discard strategy. In this systematic review and meta-analysis, we searched MEDLINE, Embase, and Scopus from database inception to June 5, 2024, without language restrictions, for diagnostic accuracy studies that assessed the performance of real-time CADx systems, compared with histology, for the optical diagnosis of diminutive polyps (≤5 mm) in the entire colon. We synthesised data for three strategies: CADx-alone, CADx-unassisted, and CADx-assisted; when the endoscopist was involved in the optical diagnosis, we synthesised data exclusively from diagnoses for which confidence in the prediction was reported as high. The primary outcomes were the proportion of polyps that would have avoided pathological assessment (ie, the proportion optically diagnosed with high confidence; main benefit) and the proportion of polyps incorrectly predicted due to false positives and false negatives (main harm), directly compared between CADx-assisted and CADx-unassisted strategies. We used DerSimonian and Laird's random-effects model to calculate all outcomes. We used Higgins I2 to assess heterogeneity, the Grading of Recommendations, Assessment, Development, and Evaluation approach to rate certainty, and funnel plots and Egger's test to examine publication bias. This study is registered with PROSPERO, CRD42024508440. We found 1019 studies, of which 11 (7400 diminutive polyps, 3769 patients, and 185 endoscopists) were included in the final meta-analysis. Three studies (1817 patients and 4086 polyps [2148 neoplastic and 1938 non-neoplastic]) provided data to directly compare the primary outcome measures between the CADx-unassisted and CADx-assisted strategies. We found no significant difference between the CADx-assisted and CADx-unassisted strategies for the proportion of polyps that would have avoided pathological assessment (90% [88-93], 3653 [89·4%] of 4086 polyps diagnosed with high confidence vs 90% [95% CI 85-94], 3588 [87·8%] of 4086 polyps diagnosed with high confidence; risk ratio 1·01 [95% CI 0·99-1·04; I2=53·49%; low-certainty evidence; Egger's test p=0·18). The proportion of incorrectly predicted polyps was lower with the CADx-assisted strategy than with the CADx-unassisted strategy (12% [95% CI 7-17], 523 [14·3%] of 3653 polyps incorrectly predicted with a CADx-assisted strategy vs 13% [6-20], 582 [16·2%] of 3588 polyps incorrectly diagnosed with a CADx-unassisted strategy; risk ratio 0·88 [95% CI 0·79-0·98]; I2=0·00%; low-certainty evidence; Egger's test p=0·18). CADx did not produce benefit nor harm for the resect-and-discard strategy, questioning its value in clinical practice. Improving the accuracy and explainability of CADx is desired. European Commission (Horizon Europe), the Japan Society of Promotion of Science, and Associazione Italiana per la Ricerca sul Cancro.