Objective To compare the effectiveness of locking plate and intramedullary nail in treatment of Neer two- and three-part fractures of the proximal humerus in the elderly. Methods A retrospective analysis was conducted on 86 elderly patients with Neer two- and three-part fractures of the proximal humerus met the selection criteria between January 2015 and December 2018. Forty-six patients were treated with locking plate fixation (locking plate group), and 40 patients with intramedullary nail fixation (intramedullary nail group). There was no significant difference in gender, age, cause of injury, fracture side and type, time from injury to operation, and comorbidities between the two groups (P>0.05). Visual analogue scale (VAS) score, American Shoulder and Elbow Surgery (ASES) score, Constant-Murley score, and shoulder range of motion (forward flexion, abduction, and external rotation) were compared between the two groups. X-ray films were taken to assess the fracture healing, and the neck-shaft angle was measured at 2 days after operation and at last follow-up, and the difference between the two time points was calculated. Results Patients in both groups were followed up 18-40 months, with an average of 30.4 months. There was no significant difference in follow-up time between the two groups (t=−0.986, P=0.327). X-ray films reexamination showed that the fractures of two groups healed, and the healing time was (11.3±2.1) weeks in locking plate group and (10.3±2.0) weeks in intramedullary nail group, which had significant difference between the two groups (t=2.250, P=0.027). The difference of neck-shaft angle was (7.63±7.01)° in locking plate group and (2.85±2.82)° in intramedullary nail group, which had significant difference between the two groups (t=4.032, P<0.001). There was no significant difference in Constant-Murley score, ASES score, VAS score, and shoulder range of motion between the two groups at last follow-up (P>0.05). Complications occurred in 13 cases (28.3%) of locking plate group and in 4 cases (10.0%) of intramedullary nail group, and the difference between the two groups was significant (χ2=4.498, P=0.034). Conclusion Both locking plates and intramedullary nails can be used for the treatment of Neer two- and three-part fractures of the proximal humerus in the elderly. The intramedullary nail fixation surgery is more minimally invasive, which has fewer postoperative complications and faster fracture healing.