The growing multidisciplinary field of tissue engineering aims at predictably regenerating, enhancing, or replacing damaged or missing tissues for a variety of conditions caused by trauma, disease, and old age. One area of research that has gained tremendous awareness in recent years is that of platelet-rich fibrin (PRF), which has been utilized across a wide variety of medical fields for the regeneration of soft tissues. This systematic review gathered all the currently available in vitro, in vivo, and clinical literature utilizing PRF for soft tissue regeneration, augmentation, and/or wound healing. In total, 164 publications met the original search criteria, with a total of 48 publications meeting inclusion criteria (kappa score = 94%). These studies were divided into 7 in vitro, 11 in vivo, and 31 clinical studies. In summary, 6 out of 7 (85.7%) and 11 out of 11 (100%) of the in vitro and in vivo studies, respectively, demonstrated a statistically significant advantage for combining PRF to their regenerative therapies. Out of the remaining 31 clinical studies, a total of 8 reported the effects of PRF in a randomized clinical trial, with 5 additional studies (13 total) reporting appropriate controls. In those clinical studies, 9 out of the 13 studies (69.2%) demonstrated a statistically relevant positive outcome for the primary endpoints measured. In total, 18 studies (58% of clinical studies) reported positive wound-healing events associated with the use of PRF, despite using controls. Furthermore, 27 of the 31 clinical studies (87%) supported the use of PRF for soft tissue regeneration and wound healing for a variety of procedures in medicine and dentistry. In conclusion, the results from the present systematic review highlight the positive effects of PRF on wound healing after regenerative therapy for the management of various soft tissue defects found in medicine and dentistry.