Background/Objectives: Polymer-free drug-eluting stents (PF-DESs) aim to mitigate long-term adverse effects associated with polymer-based platforms. However, clinical comparisons with biodegradable polymer DESs (BP-DESs) remain limited. The objective of this review is to assess the efficacy and safety of PF-DESs versus thin-struts (<100 μm) BP-DESs in patients undergoing percutaneous coronary intervention (PCI). Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing PF-DESs and BP-DESs in adults undergoing PCI. PubMed, Embase, and CENTRAL were searched up to 1 February 2025. A random-effects model was used to calculate pooled risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). Outcomes included myocardial infarction (MI), all-cause and cardiac death, target lesion revascularization (TLR), stent thrombosis, and angiographic/OCT parameters. Subgroup and sensitivity analyses were conducted for outcomes with high heterogeneity (I² > 50%). Results: Nine RCTs (n = 9597) were included. At 12 months, no significant differences were found between PF-DESs and BP-DESs for TLR (RR 1.51; 95% CI: 0.83–2.75), MI, or stent thrombosis. At 24 months, MI and all-cause death were similar between groups. A subgroup analysis showed lower cardiac death with the BioFreedom stent (RR 0.57; 95% CI: 0.35–0.90), not observed in non-BioFreedom devices. No significant differences were detected in angiographic or OCT outcomes, though heterogeneity was high. Conclusions: PF-DESs and BP-DESs demonstrated comparable clinical performance. The observed benefit in cardiac death with BioFreedom may reflect device-specific effects and merits further investigation.