Background: The optimal technique for operative fixation of humeral shaft fractures remains controversial and warrants research. Objectives: The purpose of the current study was to compare the functional and clinical outcomes of conventional open reduction and internal fixation (ORIF) with minimally invasive plate osteosynthesis (MIPO) in patients with fractures in two-third distal humeral shaft. Patients and Methods: In the current prospective case-control study, 65 patients with humeral shaft fractures were treated using ORIF (33 patients) or MIPO (32 patients). Time of surgery, time of union, incidence of varus deformity and complications were compared between the two groups. Also, the university of California-Los Angeles (UCLA) shoulder rating scale and Mayo Elbow performance score (MEPS) were used to compare the functional outcomes between the two groups. Results: The median of union time was shorter in the MIPO group (4 months versus 5 months). The time of surgery and functional outcomes based on the UCLA and MEPS scores were the same. The incidence of varus deformity was more than 5° and was higher and the incidence of nonunion, infection and iatrogenic radial nerve injury were lower in the MIPO group; however, the differences were not significant. Conclusions: Due to the shorter union time, to some extent less complication rate and comparable functional and clinical results, the authors recommend to use the MIPO technique in treating the mid-distal humeral shaft fracture.