Purpose: Analyze the impact of tranexamic acid (TXA) use after percutaneous nephrolithotomy (PCNL) on blood loss and transfusion rate (TR), and secondary outcomes, complications rate and stone-free rates (SFRs), operative time (OT), and length of hospital stay (LOS). Materials and Methods: Search made in the Medline (PubMed), Embase, and Central Cochrane for studies published up to August 2021. The study protocol was registered at prospective register of ongoing systematic reviews (CRD42020182197). Eligibility criteria were defined based on Patient, Intervention, Comparison, Outcomes, Study Design acronym (PICOS). Articles included were those who assessed the effect of intravenous TXA in patients submitted to percutaneous nephrolithotripsy (PCNL). Only randomized placebo-controlled trial that included patients with and without TXA perioperatively. Results: A total of 1151 patients were included in seven studies. Six studies presented a lower blood TR for the TXA group (p < 0.00001). Four studies presented similar results in relationship to a lower SFRs (p = 0.004) and similar results regarding overall complication rate for the control group (p = 0.03). Regarding the "major complication rate" (Clavien-Dindo ≥3), no difference was found (p = 0.07). Four studies showed a higher mean OT for the control group (159 × 151 minutes, respectively, p = 0.003). Six studies found a lower mean LOS in the TXA group (4.0 × 3.5 days, respectively, p = 0.03). Conclusions: The benefit of TXA use in the setting of PCNL perioperatively is clear. Our study showed favorable results to TXA use in relationship to TR, SFR, complication rate, OT, and LOS, but these results did not translate into a lower major complication rate. Further studies evaluating the complexity of the calculi and events unrelated to PCNL may help us select which patients will benefit from the use of TXA.