Natural circulation loop (NCL) based secondary fluid systems are simple, reliable, and inexpensive due to the absence of any moving components such as pumps. Water-based NCLs are widely used in applications such as solar collectors and nuclear reactors. Also, most of the studies on NCLs do not consider the three-dimensional (3D) variation of the field variables. In the subject work, 3D steady flow simulation of water based, single-phase rectangular NCL with isothermal source and sink has been carried out to study the effects of different design and operating parameters such as loop height, temperature lift, in plane and out of plane tilt angles on the rate of heat transfer, and the rate of entropy generation due to both fluid flow and heat transfer. The rate of entropy generation due to both heat transfer and fluid flow for turbulent flow regimes in a NCL is calculated for a wide range of design and operating parameters. In turbulent flow regimes, the rate of entropy generation due to fluid flow is significant although the rate of entropy generation due to heat transfer is dominant. All the above-mentioned design and operating parameters have significant effect on the rate of entropy generation and the rate of heat transfer as well. With increases in loop height and temperature lift, the rate of entropy generation increases. As the tilt angle increases in the XY plane, the rate of the entropy generation initially increases but after certain tilt angle it starts decreasing.