A structural investigation on some 4-amido-2-phenyl-1,2-dihydro-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, designed as human A3 adenosine receptor (hA3 AR) antagonists, is described. In the new derivatives, some acyl residues with different steric bulk were introduced on the 4-amino group, and their combination with the 4-methoxy group on the 2-phenyl moiety, and/or the 6-nitro/6-amino substituent on the fused benzo ring, was also evaluated. Most of the new derivatives were potent and selective hA3 AR antagonists. SAR analysis showed that hindering and lipophilic acyl moieties not only are well tolerated but even ameliorate the hA3 affinity. Interestingly, the 4-methoxy substituent on the appended 2-phenyl moiety, as well as the 6-amino group, always exerted a positive effect, shifting the affinity toward the hA3 receptor subtype. In contrast, the 6-nitro substituent exerted a variable effect. An intensive molecular modeling investigation was performed to rationalize the experimental SAR findings.