In the current research paper a novel hybrid model combining first-principle and artificial intelligence (AI) was developed for simulation of a chemical reactor. We study a 2-dimensional reactor with heating sources inside it by using computational fluid dynamics (CFD). The type of considered reactor is bubble column reactor (BCR) in which a two-phase system is created. Results from CFD were analyzed in two different stages. The first stage, which is the learning stage, takes advantage of the swarm intelligence of the ant colony. The second stage results from the first stage, and in this stage, the predictions are according to the previous stage. This stage is related to the fuzzy logic system, and the ant colony optimization learning framework is build-up this part of the model. Ants movements or swarm intelligence of ants lead to the optimization of physical, chemical, or any kind of processes in nature. From point to point optimization, we can access a kind of group optimization, meaning that a group of data is studied and optimized. In the current study, the swarm intelligence of ants was used to learn the data from CFD in different parts of the BCR. The learning was also used to map the input and output data and find out the complex connection between the parameters. The results from mapping the input and output data show the full learning framework. By using the AI framework, the learning process was transferred into the fuzzy logic process through membership function specifications; therefore, the fuzzy logic system could predict a group of data. The results from the swarm intelligence of ants and fuzzy logic suitably adapt to CFD results. Also, the ant colony optimization fuzzy inference system (ACOFIS) model is employed to predict the temperature distribution in the reactor based on the CFD results. The results indicated that instead of solving Navier–Stokes equations and complex solving procedures, the swarm intelligence could be used to predict a process. For better comparisons and assessment of the ACOFIS model, this model is compared with the genetic algorithm fuzzy inference system (GAFIS) and Particle swarm optimization fuzzy inference system (PSOFIS) method with regards to model accuracy, pattern recognition, and prediction capability. All models are at a similar level of accuracy and prediction ability, and the prediction time for all models is less than one second. The results show that the model’s accuracy with low computational learning time can be achieved with the high number of CIR (0.5) when the number of inputs ≥ 4. However, this finding is vice versa, when the number of inputs < 4. In this case, the CIR number should be 0.2 to achieve the best accuracy of the model. This finding could also highlight the importance of sensitivity analysis of tuning parameters to achieve an accurate model with a cost-effective computational run.