A non-healing diabetic foot ulcer (DFU) is a debilitating clinical problem amounting to socioeconomic and psychosocial burdens. DFUs increase morbidity due to prolonged treatment and mortality in the case of non-treatable ulcers resulting in gangrene and septicemia. The overall amputation rate of the lower extremity with DFU ranges from 3.34% to 42.83%. Wound debridement, antibiotics, applying growth factors, negative pressure wound therapy, hyperbaric oxygen therapy, topical oxygen, and skin grafts are common therapies for DFU. However, recurrence and nonhealing ulcers are still major issues. Chronicity of inflammation, hypoxic environment, poor angiogenesis, and decreased formation of the extracellular matrix (ECM) are common impediments leading to nonhealing patterns of DFUs. Angiogenesis is crucial for wound healing since proper vessel formation facilitates nutrients, oxygen, and immune cells to the ulcer tissue to help in clearing out debris and facilitate healing. However, poor angiogenesis due to decreased expression of angiogenic mediators and matrix formation results in nonhealing and ultimately amputation. Multiple proangiogenic mediators and vascular endothelial growth factor (VEGF) therapy exist to enhance angiogenesis, but the results are not satisfactory. Thus, there is a need to investigate novel pro-angiogenic mediators that can either alone or in combination enhance the angiogenesis and healing of DFUs. In this article, we critically reviewed the existing pro-angiogenic mediators followed by potentially novel factors that might play a regulatory role in promoting angiogenesis and wound healing in DFUs.