The objective of this study was to describe the histological artifacts caused by high-power laser use compared to cold scalpel surgery in oral soft tissue lesions. Clinical studies that evaluated and compared histological artifacts resulting from the use of high-power lasers and cold scalpels in oral soft tissue lesions biopsies were retrieved from seven databases and four grey literatures, up to July 2022. The risk of bias was investigated using the ROBINS-I tool. The certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Seven studies were eligible for qualitative analysis. Based on the results obtained, those four studies had a low risk of bias, and three studies had an unclear risk of bias. The certainty of the evidence was classified as low. Limited evidence showed that epithelial artifacts such as loss of intraepithelial and subepithelial adhesions, accompanied by pyknotic, fusiform, and/or hyperchromic nuclei, were more common when a high-power laser device was used. Four articles reported that the use of high-power lasers did not interfere with the histopathological diagnosis of oral soft tissue lesions. Due to the heterogeneity of the data, a meta-analysis was not performed. Compared to the use of cold scalpels, histological artifacts, particularly those observed in epithelial tissue, are more common when high-powered lasers are used in oral lesions biopsies. The eligibility criteria and adequate indications of high-power lasers in different oral soft tissue lesion treatments must be respected to avoid tissue artifacts that impair precise histopathological diagnosis.