Introduction In this study, we clinically and radiologically investigated whether the application of expandable nails for surgical treatment of humeral shaft fractures has an advantage over locked intramedullary nails. Methods Patients treated with intramedullary fixation due to humeral shaft fractures in our clinic were investigated retrospectively. Patients with fractures of type 12A and 12B according to the AO classification in the middle 1/3 shaft region of the humerus were divided into two groups as those receiving fixation with expandable nails and with locked intramedullary nails. The union rate, union time, Q-DASH scores, duration of surgery, and complication rates were statistically compared between the two groups. Results The study included 38 patients with clinical follow-up from among 47 patients; 20 patients received fixation with locked intramedullary nails and 18 with expandable nails. The mean age of the patients was 56.92 (19-91) years and 53% (n=20) were men while 47% (n=18) were women. During statistical evaluation, a statistically significant difference was found between the groups for union (100% and 72.2%) and complication rates (6% and 13%). More union and lower complication rates were found in patients treated with locked intramedullary nails. In comparing the mean of surgical times (71.1 and 30.2 min), expandable nails had a shorter surgical time. However, there was no statistically significant difference between the union time and Q-DASH scores between the two groups. Conclusion Locked intramedullary nails are a better fixation method than expandable nails due to the low complication rate and high rate of union. However, due to shorter surgery time, expandable nailing is an alternative method in limited cases.