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The present work focuses on response surface methodology-backed thermodynamic analysis of organic Rankine cycle (ORC) driven by low-temperature heat sources (temperatures less than 150 degrees C). The zeotropic mixture of Butane and Pentane is employed as a working fluid. Both pure fluids have zero ozone depletion potential and lower global warming potential. The second order nonlinear polynomial mathematical model was developed by RSM methodology to get the relationship between thermal efficiency of ORC and decision variables. Furthermore, the analysis of variance (ANOVA) technique was applied to get apprehend of most significant decision variables in terms of p-values and F-values. In addition, contour plots were drawn to analyze a range of decision variables in which thermal efficiency of ORC is found to be higher. The results indicate that the thermal efficiency is mostly affected by heat sink temperature, followed by isentropic efficiency of the turbine and mass fraction of zeotropic mixture.