Objective To compare the efficacy and safety of hyaluronic acid (HA) and poly-L-lactic acid (PLLA) in facial rejuvenation treatment. Methods A total of 150 patients who underwent facial rejuvenation treatment at Xianning Central Hospital from January 2022 to January 2025 were included, and they were divided into the control group and the study group by the random number table method, with 75 patients in each group. The control group was treated with HA injection, and the study group was treated with PLLA injection. The Global Aesthetic Improvement Scale (GAIS) score, Wrinkle Severity Rating Scale (WSRS) score, skin elasticity (R2 value), dermal thickness, skin barrier function and adverse event rate were compared between the two groups. Results At 1 and 3 months after treatment, the GAIS scores of the study group were lower than those of the control group, and the WSRS scores were higher than those of the control group. At 6 and 12 months after treatment, the GAIS scores of the study group were higher than those of the control group, and the WSRS scores were lower than those of the control group (P <0.05). At 6 and 12 months after treatment, the R2 value and dermal thickness of the study group were higher than those of the control group (P <0.05). At 6 and 12 months after treatment, the TEWL of the study group was lower than that of the control group, and the stratum corneum hydration was higher than that of the control group (P <0.05). The incidence of adverse events in the study group was lower than that in the control group (P <0.05). Conclusion HA has the advantages of rapid onset, immediate volume enhancement, better early wrinkle improvement and faster recovery. PLLA performs better in long-term maintenance of overall facial rejuvenation, with more prominent effects in improving skin elasticity and remodeling dermal tissue, with a lower incidence of adverse events.