The present work used ANFIS, an adaptive neuro-fuzzy inference system modeling to analyze the effect of the variable parameters of helically pierced twisted tape inserts on the Nusselt number, friction factor, and thermo-hydraulic heat exchanger tube performance. The experimental data utilized for ANFIS modeling considered a diameter ratio ranging from 0.57 to 0.80, a relative pitch ratio ranging from 0.046 to 0.107, a perforation index ranging from 5% to 20% as variable twisted tape parameters and flow parameters. The Reynolds number varies from 4000 to 30000. The analysis showed that the maximum thermo-hydraulic performance was obtained at a diameter ratio of 0.65, a relative pitch ratio of 0.085, and a perforation index equal to 10%. The result predicts that the ANFIS model and experimental results are in good agreement as they have only ±0.53% deviations.