To compare the efficacy and safety of 755-nm picosecond alexandrite laser and topical tranexamic acid (TTA) combination therapy with laser monotherapy, for the treatment of melasma and facial rejuvenation. This multicenter, randomized, double-blinded, split-face study enrolled 37 patients who presented with melasma and photoaging. Facial halves were randomized to receive either laser and TTA combination therapy or laser monotherapy. Three treatments were delivered at 4-5weeks intervals. Patients were followed up for 1, 3, and 6months post-final treatment and evaluated by blinded investigators for hemi-Melasma Area and Severity Index (hemi-MASI), facial dyschromia, skin texture, laxity, and rhytids. Daily diaries rating healing progress for 7days posttreatment and satisfaction grading were performed by all patients. Adverse events were recorded. Thirty-six patients completed the follow-up. Compared with the baseline, hemi-MASI, dyschromia, and skin texture on both halves improved significantly through the follow-up (p = 0.000). A significant difference in hemi-MASI and dyschromia between combination therapy halves and monotherapy halves was noticed at 1- and 3-month follow-ups (p < 0.05). The laser monotherapy halves displayed significantly less redness and sensitivity during the 7-day posttreatment recovery period (p < 0.05). Patients' satisfaction ratings for the combination therapy halves were higher than the monotherapy halves at 1-month follow-up (p < 0.05). No severe adverse events were observed. The picosecond alexandrite laser and TTA combination therapy demonstrated synergistic efficacy for hemi-MASI and dyschromia improvements over laser monotherapy. The optimization of the picosecond laser and TTA combination regimen needs further investigation.