A hybrid technique by using TiO2/water nanofluid together with loose-fit delta-wing twisted tape (LTT-W) was employed for heat transfer enhancement. Experiments encompassed the TiO2-water nanofluids having concentration (φ) of 0.05%–0.15 vol% and the loose-fit delta-wing twisted tapes having two different wing arrangements (co- and counter arrangement) and three loose-fit ratios (c/D) of 0.0, 0.15, and 0.2. Experimental revealed that the system with combined enhancement technique gave considerably higher heat transfer than the one without enhancement technique. This can be attributed to the combined influences of swirling flow and higher thermal conductivity of the working fluid. Heat transfer rate and thermohydraulic performance rose with the decrease of loose-fit ratio and the rise of nanofluid concentration. The maximum thermohydraulic performance (TPF) of 1.36 was obtained at c/D = 0.0 and φ = 0.15%. The Multi-Objective Optimization (MOO) was also performed to study the optimal thermohydraulic performance by using GMDH models and NSGA II algorithms. The Pareto front, which contains very useful information, were extracted for both co and counter arrangements. The Pareto fronts have recognized very accurately, the best boundary of the experimental data with respect to the lowest friction factor and highest Nusselt number.