<p>In the current research, we designed cam-shaped tubes with different aspect ratios (<i>AR</i>) using two circles with tangent lines and implemented them in staggered cross-flow tube banks with Al₂O₃-water nanofluid. Numerical studies were conducted to investigate the effects of both nanofluid and aspect ratios of cam-shaped tubes on the thermal–hydraulic performance in cam-shaped tube banks. The aspect ratios of cam-shaped tubes ranged from 1 to 2.7, volume fractions (<i>ϕ</i>) of nanofluid varied from 1 to 7%, and Reynolds numbers were changed from 100 to 500. The results revealed that the addition of Al₂O₃ nanoparticle in pure water increased the heat transfer up to 17% and the friction factor up to 20.8%. Moreover, using a cam-shaped tube with <i>AR</i> of 2.7, at <i>ϕ</i> = 7%, and <i>Re</i> = 500, reduced the friction coefficient by 77.9% and increased total thermal–hydraulic performance (<i>η</i>_t) by 29.6% compared to circular tubes in pure water. This remarkable performance potentially positions our cam-shaped tubes in nanofluid as a practical and efficient choice for next-generation heat exchangers. Furthermore, we developed two new approximating equations based on numerical simulation results to predict friction factors and Nusselt numbers for staggered cam-shaped tube banks in terms of <i>Re</i>, <i>ϕ</i>, and <i>AR</i>.</p>