Melasma is a chronic, acquired hypermelanosis that primarily affects the face. Platelet-rich plasma (PRP) and tranexamic acid (TXA) are promising treatments for melasma. However, only a few randomized clinical trials have examined the efficacy and safety of combining these therapies for melasma. We aimed to compare the efficacy and safety of combining PRP and oral TXA with those of PRP alone in the treatment of facial melasma. A randomized controlled trial was conducted at Walailak University Hospital, Nakhon Si Thammarat, Thailand, between March and September 2023. Participants with mixed-type melasma were randomly allocated in a 1:1 ratio to either group A (PRP injection alone without placebo) or group B (PRP injection with oral TXA). Therapeutic efficacy and safety assessments were performed over a 12-week follow-up period. The study included 26 participants (mean age: 45.9 years, standard deviation (±SD): 5.0) who were predominantly female (84.6%). In group A, the modified Melasma Area and Severity Index (mMASI) scores significantly decreased from a median of 4.30 interquartile range (IQR): 4.10) to 3.60 (IQR: 3.10) between week 0 and week 12, respectively. In group B, the median mMASI decreased from 6.40 (IQR: 7.80) to 3.60 (IQR: 3.70) over the same period. The median change in mMASI scores in group B (2.90, IQR: 2.40) was significantly larger than in group A (0.90, IQR: 0.60) (p < 0.001, U = 160.50). However, there were no significant differences in the physicians' global assessment (PGA), melasma quality of life scale (MelasQoL) or patient satisfaction during follow-up. Four patients (15.4%) experienced transient erythema and swelling. In group B, 1 participant (7.7%) experienced transient mild gastrointestinal discomfort after receiving oral TXA. The combination of intradermal PRP injection and oral TXA is effective for melasma, even in patients with poor prognostic treatment response factors. No serious adverse reactions were observed in either group.