Abstract Background The injection of local anesthetics, an extremely painful procedure, leads to a reduction of patients’ acceptance. Objective To investigate the efficacy and adverse reactions of 4% tetracaine gel (TG) and lidocaine-prilocaine cream (LPC) on reducing the local anesthetic injection pain for upper eyelid blepharoplasty. Methods Sixty participants were equally divided into three groups. Each patient in two treatment groups was assigned a pair of eutectic mixture of local anesthetics (EMLA) and 4% TG, and the blank control group did not receive any topical anesthetic. The primary outcome was the pain score associated with anesthetic injection. The secondary outcomes included the local cutaneous reactions and eyelid edema in 24 h postoperatively. Results The NRS score in the control group was 6.65 ± 1.60, in the 4% TG and EMLA sides of 5.75 ± 1.62 and 6.25 ± 1.48 in group A, without statistically significant (p = 0.334, 0.067, respectively). While in group B, the injection pain scores in 4% TG and EMLA sides were 4.65 ± 1.66 and 5.5 ± 1.73 (p