Background Postmastectomy lymphedema can be considered the main cause of upper extremity functional impairment in patients with breast cancer. Fatigue, pain, and limited range of motion are common symptoms. If left untreated, lymphedema causes cellulitis, which can lead to gangrene in rare cases. This study was carried out to identify and compare the therapeutic advantages of virtual reality-based exercises and proprioceptive neuromuscular facilitation for postmastectomy lymphedema. Thus, a quasi-randomized comparative study of thirty female patients with unilateral postmastectomy lymphedema was conducted. Fifteen patients performed virtual reality-based exercises as well as manual lymphatic drainage, pneumatic compression, and home programs, while the other fifteen patients performed proprioceptive neuromuscular facilitation as well as manual lymphatic drainage, pneumatic compression, and home programs. The excess arm volume between the healthy and affected limbs was estimated before and after eight sessions of treatment for both groups. In addition, the affected limb functional score was calculated. Arm volume was calculated by the truncated cone formula and girth measurements obtained by the circumferential method. The Arabic version of the QuickDASH-9 scale was used to assess extremity function. Results The excess arm volume significantly decreased in both the virtual reality group (p = 0.001) and proprioceptive neuromuscular facilitation group (p = 0.005), and there was no significant difference between the two groups (p = 0.902). Age was inversely related to the improvement percentage of the QuickDASH-9 score in the virtual reality group. The functional improvement percentage was statistically significantly different between the two groups (p = 0.045). Conclusion It can be concluded that both virtual reality and proprioceptive neuromuscular facilitation have a beneficial therapeutic effect on edema in patients with unilateral postmastectomy lymphedema; neither method was found to be superior, except virtual reality was found to be superior to proprioceptive neuromuscular facilitation in motivating patients and providing visual feedback. Trial registration ClinicalTrials.gov, NCT04185181 Registered 4 December 2019 - Retrospectively registered.