In semi-batch reactors (SBRs), exothermic reactions can still result in thermal runaway accidents due to improper process conditions. Mass transfer processes as well as the dissolution enthalpy make the thermal behavior of gas–liquid reactions more variable. This study aims to propose safety criteria for gas–liquid reactions in SBRs. A dimensionless mathematical model of the gas–liquid reaction in SBRs was firstly established to determine the thermal runaway critical conditions by considering the mass transfer process. The safety boundary diagram and temperature diagram applicable to the gas–liquid reaction were constructed, along with a procedure for determining safe operating conditions for gas–liquid reactions in SBRs. A larger mass transfer coefficient and Henry constant, which increase the accumulation of reactants in the liquid phase, will broaden the boundary of thermal runaway. When the gas dissolution process is exothermic, the dissolution process accelerates the consumption of the reactants, thereby reducing the risk of thermal runaway. Finally, a series of calorimetry experiments were carried out for the reaction between carbon dioxide and aqueous ammonia solution. Temperature diagrams were constructed, from which critical operating conditions could be determined for different scenarios. This case can serve as a reference for determining safe operating conditions for other similar reactions according to the proposed procedure.