Background: Patients undergoing hemodialysis are exposed to a wide range of physical, psychological, and social problems. One of the most important strategies for health promotion in patients is motivational interviewing. This study investigated the effect of motivational interviewing on the health status of patients undergoing hemodialysis. Materials and Methods: This single-blind, parallel, randomized, clinical trial was conducted on 57 patients undergoing hemodialysis who referred to hemodialysis centers of Alzahra and Amin Hospitals, Isfahan, Iran. The participants were selected through quota sampling method and were assigned to the experimental and control groups. The experimental group received five sessions of motivational interviewing, while the control group received five sessions of group discussion about their disease. The General Health Questionnaire (GHQ) was completed by the participants before and after the intervention. Independent t-test, paired-sample t-test, and Mann–Whitney, Chi-square, and Fisher's exact tests were used to analyze the collected data. In this study, the level of significance was 0.05. Results: Before the intervention, there was no significant difference between the mean scores of general health of the two groups (t = 0.48, p = 0.631). However, one week after the intervention, the mean score of general health in the intervention group was significantly lower than that of the control group (t = 3.12, p = 0.003). Conclusions: It can be concluded that motivational interviewing effectively improved the general health of patients undergoing hemodialysis, and using such interventions in these patients is recommended.