This observational study compared physiologic and psychological indicators of stress between two groups of 30 healthy patients undergoing either surgical or nonsurgical endodontic treatments. Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure were monitored during care sessions. The patients were asked to score their anxiety before treatment and to report pain, stress, and/or discomfort experienced during care. Variations in HR and SBP were significantly dependent on treatment group (HR: F = 6, p < 0.001; SBP: F = 4, p = 0.05). Intergroup differences increased during the active steps of the treatment, such as local anesthesia, rotary instrumentation, periradicular curettage, root filling, and field removal. Moreover, the level of stress experienced during the care procedure was correlated to the level of anticipated anxiety in both groups. This study raises questions on the indications for anxiolysis or sedation in endodontic patients as a means of preventing the neurophysiologic consequences of stress.