Erectile dysfunction (ED), an unusual sexual condition in which the person fails to attain or sustain an erectile penis, severely impacts personal relationships, confidence, and efficiency. To date, low-intensity extracorporeal shock wave therapy (Li-ESWT) is an option to manage ED; however, it is associated with adverse events such as bruising, redness, and pain. Hence, in this study, we applied platelet-rich plasma (PRP), a blood-derived biomaterial containing cargo of growth factors, to enhance the therapeutic efficacy of Li-ESWT on ED. We assessed the synergistic effect of PRP+Li-ESWT, in which Li-ESWT was extracorporeally applied simultaneously with PRP. They were evaluated clinically at 22 ± 2, 50 ± 2 and 78 ± 2 days. Statistical analysis was performed using a non-parametric test, Friedman repeated measures as an alternative non-parametric test of ANOVA test. The international index of erectile function (IIEF-5) and erection hardness score (EHS) were recorded. IIEF-5 score in the pre-treated group was 8.36 ± 1.44. After 22 ± 2 days of synergistic PRP+Li-ESWT treatment, the score was 14.45 ± 2.12 (p < 0.028). This score further increased to 15.45 ± 1.93 (p < 0.008) and 16.18  ± 1.48 (p < 0.001) after 50 ± 2 days and 78 ± 2 days of treatment, respectively. The mean pre-treated EHS was 1.64 ± 0.20 (p < 0.002), which increased to 2.81 ± 0.26 (p < 0.002), 3.09 ± 0.25 (p < 0.0002) and 3.18 ± 0.12 (p < 0.000) on day 22 ± 2, 50 ± 2 and 78 ± 2 days, respectively. Conclusively, our study demonstrated potent synergistic therapy of PRP+Li-ESWT in ED treatment by improving IIEF-5 and EHS scores. However, extensive mechanism-based clinical studies are needed to reach a consensus.