Artificial intelligence (AI) shows considerable promise in the areas of lymphoma diagnosis, prognosis, and gene prediction. However, a comprehensive assessment of potential biases and the clinical utility of AI models is still needed.Our goal was to evaluate the biases of published studies using AI models for lymphoma histopathology and assess the clinical utility of comprehensive AI models for diagnosis or prognosis.This study adhered to the Systematic Review Reporting Standards. A comprehensive literature search was conducted across PubMed, Cochrane Library, and Web of Science from their inception until August 30, 2024. The search criteria included the use of AI for prognosis involving human lymphoma tissue pathology images, diagnosis, gene mutation prediction, etc. The risk of bias was evaluated using the Prediction Model Risk of Bias Assessment Tool (PROBAST). Information for each AI model was systematically tabulated, and summary statistics were reported. The study is registered with PROSPERO (CRD42024537394) and follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 reporting guidelines.The search identified 3565 records, with 41 articles ultimately meeting the inclusion criteria. A total of 41 AI models were included in the analysis, comprising 17 diagnostic models, 10 prognostic models, 2 models for detecting ectopic gene expression, and 12 additional models related to diagnosis. All studies exhibited a high or unclear risk of bias, primarily due to limited analysis and incomplete reporting of participant recruitment. Most high-risk models (10/41) predominantly assigned high-risk classifications to participants. Almost all the articles presented an unclear risk of bias in at least one domain, with the most frequent being participant selection (16/41) and statistical analysis (37/41). The primary reasons for this were insufficient analysis of participant recruitment and a lack of interpretability in outcome analyses. In the diagnostic models, the most frequently studied lymphoma subtypes were diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma, while in the prognostic models, the most common subtypes were diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, and Hodgkin lymphoma. In the internal validation results of all models, the area under the receiver operating characteristic curve (AUC) ranged from 0.75 to 0.99 and accuracy ranged from 68.3% to 100%. In models with external validation results, the AUC ranged from 0.93 to 0.99.From a methodological perspective, all models exhibited biases. The enhancement of the accuracy of AI models and the acceleration of their clinical translation hinge on several critical aspects. These include the comprehensive reporting of data sources, the diversity of datasets, the study design, the transparency and interpretability of AI models, the use of cross-validation and external validation, and adherence to regulatory guidance and standardized processes in the field of medical AI.©Yao Fu, Zongyao Huang, Xudong Deng, Linna Xu, Yang Liu, Mingxing Zhang, Jinyi Liu, Bin Huang. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 14.02.2025.