The first-line treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has recently undergone major changes, and targeted therapies have ushered in a new era of CLL/SLL treatment. Scientists in different countries have successively analyzed the efficacy of various drugs, but safety studies are relatively insufficient. Therefore, this systematic evaluation and retrospective meta-analysis was conducted to compare the differences in adverse effects and their incidence among first-line treatment regimens for CLL/SLL. We searched the Cochrane Library, PubMed, Web of Science, and Embase databases, with a cutoff date of December 2023. Frequency-based network meta-analysis was performed using STATA 16.0, and the risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool (RoB2.0). Thirty-seven randomized controlled trials involving 15,557 patients were included, and the results showed that, compared with other regimens, zanubrutinib had a lower probability of causing adverse hematologic effects and a lower probability of causing severe anemia (SUCRAs: 79. 6%), all-grade anemia (SUCRAs: 87.2%), severe thrombocytopenia (SUCRAs: 97.0%), all-grade thrombocytopenia (SUCRAs: 90.6%), severe neutropenia (SUCRAs: 91.8%) and all-grade neutropenia (SUCRAs: 86.6%) than the other regimens. The higher rates of adverse reactions seen with each of the other first-line regimens were not concentrated in any single regimen. The second-generation BTK inhibitors may have a lower probability of causing hematologic adverse reactions. However, its adverse effects in other systems are still noteworthy. The cardiovascular toxicity of venetoclax combination regimens should not be overlooked.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.