Methemoglobinemia is a potentially life-threatening rare medical condition, which refers to an increase in the level of oxidized form of hemoglobin (methemoglobin). Excessive replacement of hemoglobin with methemoglobin leads to functional hypoxia and even fatal conditions. The aim of this study was to evaluate the effect of two common local anesthetic agents namely lidocaine and articaine administered for hemostasis during surgery on methemoglobin level. This prospective cohort study was conducted from January 2017 to December 2019. Demographic data including age, gender, and weight of patients were collected. Sixty patients were randomly divided into three groups (n=20) regarding the local anesthetic agent administered for hemostasis during surgery as lidocaine group (group 1), articaine group (group 2), and control group (no local anesthetic; group 3). The patients were candidates for orthognathic surgery, reconstruction of the maxillary and mandibular atrophic ridges with autogenous grafts, and reconstruction of maxillofacial fractures. The methemoglobin level was measured before surgery and six hours after the initiation of surgery. The mean age and weight of patients were not significantly different among the three groups (p= 0.891 and p= 0.416, respectively). No significant differences were observed among the three groups regarding the gender distribution (p= 0.343) or type of surgery (p= 0.990). Statistical analysis did not show any significant difference in the mean baseline methemoglobin level among the three groups (p= 0.109). Although the mean methemoglobin values increased in the three groups, paired sample t-test did not show any significant change in the values at six hours after the initiation of surgery compared with baseline in any of the three groups (p= 0.083 for group 1, p= 0.096 for group 2, and p= 0.104 for group 3). The results demonstrated that administration of lidocaine and articaine plus epinephrine for hemostasis during general anesthesia are equally safe.