This study examines the use of a1 mm-diameter tubular microreactor submerged in a temperature-controlled water bath to activate potassium persulfate (KPS) via thermal, Fe2+-catalyzed, and combined thermo-catalytic processes for degrading the persistent textile dye Safranin O (SO). The efficiency of these methods was evaluated under varying conditions, including KPS, dye, and Fe2⁺ flow rates, solution pH, reactor length, and water matrix quality (deionized water, tap water, seawater, and secondary effluent from a wastewater treatment plant (SEWWTP)) across bath temperatures of 30–80 °C. Total organic carbon (TOC) analysis validated the results. Maximum dye conversion (up to 89%) occurred at 70 °C, with no improvement beyond this temperature, mainly due to radical-radical recombination. Longer reactors (2–6 m) enhanced conversion, though this effect diminished at higher temperatures due to efficient thermal activation. Increasing dye flow rates reduced removal efficiency, particularly above 50 °C, highlighting kinetic and mass transfer limitations. Persulfate flow rate increases improved conversion, but a plateau emerged at 80 °C. At lower temperatures (30–40 °C), Fe2+ addition significantly boosted SO conversion in deionized water. Between 40 and 50 °C, conversion rose from 30.27% (0 mM Fe2+) to 85.91% (0.2 mM Fe2+) at 50 °C. At higher temperatures (60–80 °C), conversion peaked at 70 °C for lower Fe2+ concentrations (100% for 0.01–0.05 mM Fe2+), but higher Fe2+ levels (0.1–0.2 mM) caused a decline above 60 °C, dropping to 68.44% for 0.2 mM Fe2+ at 80 °C. Deionized, tap, and mineral water showed similar performance, while river water, secondary effluent, and seawater inhibited SO conversion at lower temperatures (30–60 °C). At 70–80 °C, all matrices achieved efficiencies comparable to deionized water for both thermal and thermo-catalytic activation. The thermo-catalytic system achieved >50% TOC reduction, indicating significant organic matter mineralization. The results were comprehensively analyzed in relation to thermal and kinetic factors influencing the performance of continuous-flow reactors.