This study experimentally and analytically investigates the thermal performance enhancement of shell-and-tube heat exchangers using nanofluids, with a focus on conjugate heat transfer analysis. Five nanoparticle types (Al₂O₃, ZnO, SiO₂, CuO, and TiO₂) dispersed in distilled water and ethylene glycols were evaluated. The conjugate analysis integrates fluid-thermal-structural interactions, revealing that ethylene glycol-based nanofluids exhibit more stable heat transfer characteristics (19.83% deviation in HTC from theory) compared to water-based systems (93.33% deviation). SiO₂ nanoparticles showed consistent performance across all parameters, while CuO displayed significant variability in ethylene glycol (LMTD deviations up to 14.68%). The study highlights limitations in theoretical models, particularly at higher nanoparticle concentrations (4–5%), where particle aggregation and interfacial thermal resistance dominate. Conjugate modeling demonstrated that water-based nanofluids achieve 10X higher heat flux than ethylene glycol due to superior conductivity, though EG’s lower viscosity reduces pumping costs.