Organic　Rankine　cycle　(ORC)　is　a　promising　power　cycle　to　convert　low-grade　thermal　energy.　The　quick　and　easy　evaluation　of　the　potential　working　fluids　lacking　thermophysical　property　data　is　important　for　the　working　fluid　selection　of　ORC.　This　paper　proposes　a　systematic　framework　of　working　fluid　evaluation　from　the　molecular　structure　perspective,　which　couples　the　quantitative　structure　property　relationship　(QSPR)　and　universal　equations　of　state.　The　thermodynamic　performance　of　ORC　is　first　correlated　with　four　key　thermophysical　properties　based　on　universal　equations　of　state.　Then,　these　thermophysical　properties　are　obtained　from　the　corresponding　QSPR　models　based　on　the　molecular　structure　of　working　fluids.　The　influence　factors　of　ORC　performance　at　a　micro　level　are　investigated　using　the　QSPR　models.　Moreover,　the　effects　of　molecular　characteristics　on　thermal　efficiency　are　analyzed.　The　criteria　for　working　fluid　design/selection　are　recommended　aiming　at　the　improvement　of　thermal　efficiency.　The　proposed　framework　shows　sufficient　accuracy　with　the　relative　errors　of　−0.41　-　15.85%　and　mean　absolute　error　of　8.29%　compared　with　the　results　based　on　REFPROP.　It　is　found　that　the　cyclization　of　carbon　chain　is　an　ideal　method　for　the　working　fluid　design　based　on　alkanes　and　alkenes.　This　work　can　provide　new　insights　for　the　evaluation,　selection,　and　design　of　working　fluids　on　the　molecular　structure　level.　©　2023