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A three-dimensional computational fluid dynamics (CFD) study is carried out to explore the effect of duct cross section on the thermo-hydraulic performance of various ducts. A finite volume-based scheme with an SST k-omega model and mixture model (two-phase model) was used to obtain more realistic results. A two-phase mixture model was used to consider the movement between base fluid and nanoparticles. Al2O3 nanoparticle having a volume fraction of 0.01% and 42 nm as particle size, the heat transfer and friction factor characteristic are studied for turbulent flow regime (3000 < Re < 9000) with variable thermo-physical properties. A maximum enhancement of 86% in heat transfer rate is obtained for the serpentine duct compared to the conventional circular duct at Re = 4500. Owing to a significantly lower increase in pressure drop, the elliptical duct has the highest thermo-hydraulic performance parameter of 1.54 relative to the circular duct. Further, to analyze the heat transfer quality, the entropy generation rate is studied, and it is observed that the square duct reported the highest with an increase of 60% and the elliptical duct the lowest with a reduction of 54% relative to the circular duct. This study can aid in choosing the duct geometry to enhance the heat transfer rate with nanofluid for applications such as solar-thermal, heat exchangers, etc. [ABSTRACT FROM AUTHOR]