Background: The first step in efficient application of novel teaching methods is identification of barriers and challenges in order to perform appropriate interventions. Various studies have emphasized the utilization of novel methods in instruction of nursing students. However, there are barriers and challenges against the use of these techniques. Therefore, the present study aimed to investigate the challenges and executive barriers against the utilization of novel approaches in instructing nursing students from the perspective of nursing instructors. Methods: In this descriptive-analytical study, 150 nursing instructors were selected through census from three nursing schools in Fars province, southwest of Iran in 2019. The study data were entered into the SPSS 22 software and were analyzed using statistical tests, frequency distribution, mean, standard deviation, t-test, and one-way ANOVA. Results: The effective challenges against the utilization of novel teaching methods were classified into three domains as follows: challenges related to students, challenges related to instructors, and structural-managerial challenges. Considering the challenges associated with students, the highest score was related to the students’ lack of familiarity with novel teaching methods. Regarding the challenges associated with instructors, the highest scores were related to the instructors’ unfamiliarity with novel teaching methods and lack of mastery and skills. Finally, the large number of students and lack of support and encouragement on the part of educational institutions obtained the highest scores in the field of structural-managerial challenges. The results of independent t-test revealed a significant relationship between gender and educational degree in all three domains (p<0.001). The results also showed a significant relationship between work experience and the scores of the three domains (p<0.001). Conclusion: Application of novel approaches in nursing education requires infrastructures as well as elimination of executive barriers. Instructors’ and students’ familiarity with novel techniques and their execution processes and educational institutions’ support could contribute to the effectiveness of these methods, as well.