Melasma therapy remains challenging due to limited effectiveness, side effects, and relapses. Topical tranexamic acid (TXA) is promising but requires further research to optimize its formulation. Alongside the therapeutic benefit of fractional CO2 laser (FCL) in melasma, FCL and microneedling (MN) are recognized methods for transepidermal drug delivery. Nanotechnology-based topicals can enhance drug penetration and reduce side effects. Objectives were to evaluate and compare the effectiveness of combined FCL- or MN-assisted transepidermal delivery of TXA 3% gel and FCL monotherapy versus nanotechnology-based TXA 1% microemulsion monotherapy in melasma treatment. Fifty-two melasma females were divided randomly into three groups (A, B & C) for a five-month treatment. Group A (n = 20), using a split-face design, received FCL on the right side (A1) and MN on the left (A2), both with TXA 3% gel applied post-session and daily. Group B (n = 21), also with a split-face design, received FCL with TXA 3% gel post-session only on the right side (B1), while the left side (B2) received FCL alone. Group C (n = 11) received TXA 1% microemulsion daily for the whole face. Evaluations included clinical, dermoscopic, and immunohistochemical SOX10 assessments, with a three-month follow-up. All groups showed a significant reduction of Hemi Melasma Area and Severity Index (Hemi-MASI), dermoscopic, and SOX10 immunoreactivity scores. Groups A1, A2, and C exhibited greater improvement compared to B1 and B2. No recurrence occurred during follow-up. Concluding that TXA 1% microemulsion is effective and safe, procedure-free monotherapy with outcomes comparable to FCL- and MN-assisted TXA 3% gel delivery for melasma.