Background/Objectives: Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) is intended to restore reparative signaling in diabetic wounds, yet its efficacy and the contribution of delivery systems remain uncertain. This systematic review evaluated its preclinical efficacy, mechanistic responses, safety, risk of bias, certainty, and attribution of effects. Methods: Following PRISMA 2020 and an OSF-registered protocol, PubMed, Embase, Scopus, Web of Science, and ScienceDirect were searched from inception to 29 July 2026 for controlled in vivo diabetic wound studies. Compatible outcomes were pooled using random-effects models with restricted maximum-likelihood estimation and Hartung–Knapp adjustment. Non-poolable findings were synthesized using attribution-specific effect direction maps. Risk of bias and certainty were assessed with SYRCLE and preclinical GRADE, respectively. Results: Twenty-nine studies were included from 3844 records. For percentage wound closure at days 10–12, three studies comprising 113 animals yielded a favorable but imprecise pooled estimate (mean difference: 12.94 percentage points; 95% CI: −0.34 to 26.23; p = 0.052; I² = 54.6%). Two studies comprising 45 animals suggested a non-significant 4.28-day reduction in time to complete closure (95% CI: −27.98 to 19.42). In the exploratory effect direction synthesis, directly attributable macroscopic healing showed a favorable direction in 17 of 22 studies and was the only domain meeting the prespecified 70% concordance threshold; four of these studies had confirmed unit-of-analysis concerns, and other reparative domains were heterogeneous. Formulation-level comparisons met the same exploratory threshold across four reparative domains, but the isolated contribution of rhPDGF-BB could not be determined. Safety reporting was sparse. Certainty for the primary outcome was very low. Conclusions: Directly attributable comparisons showed a predominantly favorable study-level pattern for macroscopic wound healing in the exploratory synthesis, but the pooled effects were imprecise and inconclusive. Formulation-level comparisons suggested broader reparative activity, although the independent contribution of rhPDGF-BB could not be isolated. Better controlled and clinically representative studies are required before confident translation.