This study aims to investigate the effect of heat load, tilt angle, and volume concentration of alumina nanofluid on the thermal performance enhancement of cylindrical screen mesh wick heat pipe in terms of thermal resistance(R) and thermal conductivity(k). Response surface methodology based on the Box–Behnken design was implemented to investigate the influence of heat input (100–200 W), tilt angle (0–90°), and volume concentration (0.05–0.25 vol%) of nanofluid as the independent variables. Second-order polynomial equations were established to predict the responses, ‘R’, and ‘k’. The significance of the models was tested by means of analysis of variance (ANOVA). In addition, a correlation between the independent variables was derived in this study. The results revealed that the optimum heat input, inclination angle, and concentration of nanofluid were determined as 200 W, 52.72°, and 0.1773 vol. % respectively for both ‘R’ and ‘k’. SEM analysis was performed to observe the thermal performance phenomena of the heat pipe before and after experimentation.