This study aimed to compare the efficacy of three methods for isolated greater tuberosity fractures of the humerus. A retrospective review of patients with isolated humeral greater tuberosity fractures between January 2013 and June 2021 in our institution. We recorded data on patient demographics, injury characteristics, preoperative and postoperative imaging findings, length of incision, operative time, and intraoperative blood loss. A total of 107 patients met the inclusion criteria and were divided into three groups. 50 patients in group A were administered a proximal humeral internal locking system (PHILOS) plate fixed using the deltopectoral approach, 26 patients in group B were administered a PHILOS plate fixed using the deltoid-splitting approach, and 31 patients in group C were administered a novel anatomical plate fixed using the deltoid-splitting approach. No significant differences were identified in sex, age, injury mechanism, type of fracture, dominant side limb, or shoulder anterior joint dislocation. However, the operative time, blood loss, and the length of incision was shorter than in Group C. Moreover, pain was evaluated on the third and fifth days after surgery; pain was lower in Group C, and pain at the last follow-up was not different between the groups. No significant differences were identified in the Constant score, DASH score, and ROM at the last follow-up. 2 patients were diagnosed with subacromial impingement, 1 in Group A one in Group B, and 1 patient in Group B experienced axillary nerve injury after surgery. The novel anatomical plate fixed using the deltoid-splitting approach can achieve good results in the treatment of isolated humeral greater tubercle fractures with less blood loss, shorter operative time, and shorter surgical incisions, and can relieve pain in the early postoperative period.