We conducted a systematic review to evaluate the effect of high-flow nasal oxygen and conventional oxygen therapy during procedural sedation amongst adults and children. We searched MEDLINE, EMBASE and CINAHL for randomised controlled trials that reported the effects of high-flow nasal oxygen during procedural sedation. The primary outcome measure was hypoxaemia and the secondary outcomes were minimum oxygen saturation; hypercarbia; requirement for airway manoeuvres; and procedure interruptions. The quality of evidence was assessed using the revised Cochrane risk-of bias tool and grading of recommendations, assessment, development and evaluation (GRADE). Nineteen randomised controlled trials (4121 patients) including three in children were included. Administration of high-flow nasal oxygen reduced hypoxaemia, riskratio (95%CI) 0.37 (0.24-0.56), p < 0.001; minor airway manoeuvre requirements, risk ratio (95%CI) 0.26 (0.11-0.59), p < 0.001; procedural interruptions, risk ratio (95%CI) 0.17 (0.05-0.53), p = 0.002; and increased minimum oxygen saturation, mean difference (95%CI) 4.1 (2.70-5.50), p < 0.001; as compared with the control group. High-flow nasal oxygen had no impact on hypercarbia, risk ratio (95%CI) 1.24 (0.97-1.58), p = 0.09, I2 = 0%. High-flow nasal oxygen reduced the incidence of hypoxaemia regardless of the procedure involved, degree of fractional inspired oxygen, risk-profile of patients and mode of propofol administration. The evidence was ascertained as moderate for all outcomes except for procedure interruptions. In summary, high-flow nasal oxygen compared with conventional oxygenation techniques reduced the risk of hypoxaemia, increased minimum oxygen saturation and reduced the requirement for airway manoeuvres. High-flow nasal oxygen should be considered in patients at risk of hypoxaemia during procedural sedation.