Transnasal endoscopy can cause pain or discomfort for the patient. Topical anesthetic has been used in an attempt to reduce this. However, there is no consensus on whether topical anesthetic is effective in optimizing patient experience during the procedure. The goal of this study was to perform a systematic review with meta-analysis of the efficacy of topical anesthetic on pain and comfort outcomes during endoscopy. Two authors independently searched the databases from inception to September 2013. Studies comparing topical anesthetic with placebo where the outcomes of interest were pain, comfort, or side effect outcomes were included. Sufficient data for meta-analysis were retrieved for ten trials with a total of 837 patients. The evidence suggests that local anesthetic alone or in combination with a vasoconstrictor is beneficial to patients' pain [standardized mean difference (SMD) = -0.21; p = 0.045] and comfort (SMD = -0.51; p < 0.001) outcomes when performing transnasal endoscopy. However, the topical anesthetic caused unpleasant sensation with respect to an unpleasant taste (SMD = 0.77; p < 0.001). In addition, there was no significant difference between a topical anesthetic spray and cotton type in pain and discomfort values. Applying topical anesthetic during transnasal endoscopy could reduce pain and discomfort. The spray and cotton type methods of topical anesthetic preparation showed no significant difference in terms of pain and discomfort during the procedure. However, further trials with good research methodology should be conducted to confirm our results.