The continued use of fossil fuels in internal combustion engines (ICEs) and the increasing number of active vehicles contribute to a range of problems, including environmental footprint, global warming, environmental issues, and threats to human health. Therefore, it is essential to identify and utilize alternative fuels that can replace fossil-based fuels in ICEs. In this study, long-chain amyl alcohol, a by-product of ethanol production (considered waste), is used as an alternative fuel in a spark-ignition (SI) engine. This study addresses the lack of research on the combined effects of compression ratio (CR) variation and titanium dioxide (TiO2)-assisted 2-propanol use in waste-derived amyl alcohol–gasoline blends in SI engines, particularly from thermodynamic and environmental impact perspectives. In the experimental study, the effects of CR and TiO2 nanofluid usage on performance, emissions, energy, exergy, sustainability, environmental and enviroeconomic impact are investigated in an SI engine operating with a gasoline/amyl alcohol blend. In the study, 20 % amyl alcohol (A20) by volume is used in gasoline, while TiO2 nanofluid is used at 5 ml (A20Ti5) and 10 ml (A20Ti10) per liter, respectively. Among the experimental operating parameters, the engine torque changes from 1 Nm to 4 Nm (four different loads), while the CR changes from 7:1 to 8.5:1 (two different CRs). The best overall results are generally achieved with the A20Ti10 fuel. Under high CR conditions, the A20Ti10 fuel reduces specific fuel consumption by an average of 15.5 % and increases thermal efficiency by an average of 21.9 %. A maximum reduction of 24 % in exergy destruction (at 1 Nm) and a maximum improvement of 29.7 % in exergy efficiency (at 1 Nm) are observed. Additionally, under low CR conditions, the total environmental impact decreases by an average of 5.5 % (with A20Ti5 fuel), while increasing the CR adversely affects the environmental impact. Conversely, the enviroeconomic impact shows an average reduction of 24 % under high CR conditions (with A20Ti10 fuel).