This paper presents the process design and assessment of a sugarcane-based ethanol production system that combines the usage of both mass and heat integration (pinch analysis) strategies to enhance the process efficiency and renewability performance. Three configurations were analyzed: (i) Base case: traditional ethanol production (1G); (ii) mass-integrated (1G2G); and (iii) mass and heat-integrated system (1G2G-HI). The overall assessment of these systems was based on complementary approaches such as mass and mass–heat integration, energy and exergy analysis, exergy-based greenhouse gas (GHG) emissions, and renewability exergy criteria. The performances of the three cases were assessed through five key performance indicators (KIPs) divided into two groups: one is related to process performance, namely, energy efficiency, exergy efficiency, and average unitary exergy cost (AUEC), and the other one is associated to environmental performance i.e., exergy-based CO2-equation emissions and renewability exergy index. Results showed a higher exergy efficiency of 50% and the lowest AUEC of all the systems (1.61 kJ/kJ) for 1G2G-HI. Furthermore, the destroyed exergy in 1G2G-HI was lower by 7% and 9% in comparison to the 1G and 1G2G cases, respectively. Regarding the exergy-based GHG emissions and renewability performance (λindex), the 1G2G-HI case presented the lowest impacts in terms of the CO2-equivalent emissions (94.10 gCO2-eq/MJ products), while λindex was found to be environmentally unfavorable (λ = 0.77). However, λindex became favorable (λ > 1) when the useful exergy of the byproducts was considered.