Due to strong tectonic activity, the Simao Basin frequently experiences earthquakes with a magnitude of 6 or greater. This study investigated the hydrochemical characteristics of 21 thermal springs in the Simao Basin from 2018 to 2020 to determine how the 2018 Mojiang M5.9 earthquake caused hydrochemical changes. The results showed that the Simao Basin contained saline spring waters, HCO3−-rich spring waters, and SO42−-rich spring waters. Stratum lithology characteristics in the area exerted obvious control over the water chemistry characteristics. Saline springs flowed through red beds and dissolved large amounts of halite, which is rich with Cl−and Na+. Ca2+ (Mg2+) and HCO3− in the hot spring waters were mainly derived from the dissolution of carbonate minerals, gypsum, and anhydrite in Triassic rocks. The higher SO42− content in the hot spring waters was influenced by pyrite contained in Ailaoshan metamorphic rocks. The reservoir temperatures (121–289° C) in the Simao Basin were estimated by the silica-enthalpy mixing model equation and silica-enthalpy diagram. The hot springs with higher reservoir temperatures (> 250° C) were mainly located at the edges of the basin, which may correlate with nearby deep faults that provided deep heat and metamorphic rocks with low permeabilities. The concentrations of Ca2+ and HCO3− in most springs increased obviously before the Mojiang M5.9 earthquake but decreased after the earthquake. Changes also occurred in the reservoir temperatures of some spring samples. These hydrogeochemical variations might be attributable to accelerated water-rock interactions and/or the mixing of second fluids due to the earthquake.