Millions of people throughout the world suffer from the acquired condition of hyperpigmentation known as melasma. Melasma is characterized by symmetrically oriented hyperpigmented macules and patches. Many treatment options are available with variable degrees of efficacy and tolerability. The aim of the work was to evaluate and compare the effectiveness and safety of intradermal tranexamic acid (TXA) versus intradermal platelet-rich plasma (PRP) in the treatment of various types of melasma. The current split-face prospective study included 40 cases with melasma. Tranexamic acid (TXA) was injected intradermally into the right side of the face by using a concentration of 4 mg/ml, while platelet-rich plasma (PRP) was injected intradermally into the left side. In both sides, a total of three sessions of treatment were provided, once every 4 weeks. Digital photographs were taken before each treatment session and 3 months after the last session. The modified melasma area severity index (mMASI) grading system and dermoscopy were used to assess the improvement in the condition. The disease severity and percentage of improvement were assessed by mMASI score before and after therapy across both sides of the face. along with determining the degree of satisfaction and side effects among the included cases. The mean mMASI score before therapy in the TXA side was 4.59 ± 2.87, while in the PRP side, the mean mMASI score before therapy was 4.72 ± 2.72 with no statistically significant difference between the two sides (p = 0.841). After 3 months of treatment, the mean mMASI score in the TXA-treated side was 2.49 ± 1.58 with a mean percentage of decrease of 45.67 ± 8.10%, while in the PRP side, the mean mMASI score after treatment was 2.17 ± 1.41 with a mean percentage of decrease of 53.66 ± 11.27%. There was a high statistically significant decrease in the mMASI score after treatment on both sides (p < 0.001); however, the percentage of score reduction in the PRP side compared to the TXA side was statistically higher. Intradermal injection with PRP revealed higher efficacy in the treatment of melasma as compared to TXA injection with no significant difference regarding the associated side effects.