<p>A complete evaluation approach for nanoparticle-assisted cascade refrigeration systems (CRSs) is still lacking in the literature. As a remedy to this gap, this paper presents three main innovations that are not yet covered in the literature. To the best of the authors’ knowledge, it provides the first complete 4E (energy, exergy, economic, and environmental) evaluation of an ultra-low-temperature (ULT) CRS operating with Ag-nanoparticle-doped, low-GWP refrigerants. Also, it conducts the first specific exergy costing (SPECO)-based exergoeconomic optimization for nanoparticle-containing refrigerants, directly linking exergy destruction to cost formation in ULT cascade operation. Lastly, it introduces clustering effects into the analysis, assessing how aggregation intensity alters thermodynamic and cost performance—an aspect that has not previously been addressed in any CRS study. Together, these contributions establish a comprehensive framework that significantly advances the current state of research on nanoparticle-augmented ULT CRSs. Results reveal that nanoparticle addition leads to improved system performance, with R170/R1311 enhancing coefficient of performance (COP) by 9.42–12.94% and exergy efficiency by 9.40–12.88%, R170/R161 decreasing overall product cost by 5.46–8.06%, and R170/RE170 having lowest total equivalent warming impact (TEWI) with reduction ranging from 2.52 to 12.78%. Nevertheless, particle clustering leads to overall degradation with decreased exergy efficiency ranging from 3.48 to 6.65%, decreased COP ranging from 5.75 to 6.60%, and increased total product cost rate ranging from 5.27 to 5.77%. Compared to some recently published studies on CRS with COP ranging from 0.689 to 0.750, it is observed that nano-modified model exhibits significantly enhanced performance with improved COP value of 0.799, indicating its tremendous thermodynamic performance advantage.</p>