Background Ultrasound (US) guided transoral biopsy is a novel and safe procedure for obtaining tissue in patients with oral masses. However, this procedure is less commonly used in comparison to US guided transcutaneous biopsy. The aim of this study is to compare the efficacy and safety of US-guided transoral and transcutaneous core needle biopsy (CNB) in patients with oral masses. Methods From November 2019 to March 2021, consecutive patients with oral masses were randomly assigned to undergo US-guided transoral CNB (transoral group) and US-guided transcutaneous CNB from a submental approach (transcutaneous group). During the operation, procedure time, intra-operative blood loss volume, diagnostic performance, rate of complications and pain level were recorded and compared. Results There were 112 patients (62 in the transoral group and 50 in the transcutaneous group) evaluated in this study. The postprocedural complication rate of the transcutaneous group was significantly higher than the transoral group (24% vs. 0%, P = 0.000). There was no significant difference in accuracy (95.2% vs. 88%, P = 0.30), biopsy time (76 +/- 12 s vs. 80 +/- 13 s, p = 0.09), blood losses (2.6 +/- 0.5 mL vs. 2.7 +/- 0.4 mL, p = 0.17) and visual analogue score (p = 0.327 and p = 0.444 before and after the sampling procedure) between the two groups. Conclusion US-guided transoral CNB results in high rates of technical success and lower rates of postprocedural complications.