Management of keloid is still a challenge. Many treatment modalities are available, yet no definitive treatment protocol exists. Vitamin D3 (Vit. D3) has an anti-inflammatory role in preventing tissue fibrosis. Platelet-rich plasma (PRP) contains plentiful various peptides that have anti-inflammatory and tissue repair activities. The study aimed to assess the safety and efficacy of injecting either Vit. D3 or PRP versus their combination in keloid treatment. There were sixty keloid patients in all, randomly split into three matched groups for this research. Group I received an intralesional vitamin D3 injection; Group II got an intralesional PRP. While group III received both alternatively. All patients received treatment session biweekly until clinical cure or for a maximum of 4 successive sessions. Therapeutic efficacy was assessed by Verbal rating scale (VRS), Vancouver scar scale (VSS), dermoscopic, and ultrasonic examinations. Additionally, H&E and immunohistochemical expression of Caveolin-1 (Cav-1) were studied. Significant improvements in both VSS and VRS of keloid scars were detected in the three groups studied. These findings were significantly higher among patients treated by combined Vit. D3 and PRP followed by Vit. D3 monotherapy, and lastly PRP monotherapy. Parallel dermoscopic and radiological findings were detected confirming the clinical results. In the three groups studied, histopathological examination reported significant reduction in collagen with more compact orientation, and significant increase of Cav-1 immunohistochemical expression in keloid scars after treatment. Intralesional injection of either Vit. D3, PRP or their combination are safe and effective in keloid treatment.