Alkaline phosphatase (ALP) and α-amylase are clinically relevant biomarkers for metabolic disorders, including diabetes and hepatobiliary dysfunction. This study reports the synthesis of sulfanilamide-linked triazolo–oxadiazole derivatives (7a–j) using click chemistry and their evaluation as dual enzyme inhibitors. Spectroscopic analysis were employed to validate structure of the synthesized compounds. Biological evaluation revealed that all compounds exhibited moderate inhibition against both enzymes. Compound 7e demonstrated the lowest IC50 against α-amylase at 48.11 µM, while compound 7i showed the lowest IC50 against ALP at 41.99 µM. In silico methods, were employed to guide compounds prioritization and interpret experimental outcomes. Docking scores ranged from − 8.4 to − 9.4 kcal/mol for α-amylase and − 8.3 to − 9.0 kcal/mol for ALP, consistent with experimental trends. DFT analysis revealed that smaller HOMO-LUMO gaps (3.92–4.55 eV) were correlated with enhanced chemical reactivity. ADMET profiling revealed that high TPSA values (163.47–172.70 Ų), predict low GI absorption, an inherent trade-off between polarity required for binding and membrane permeability, hence best suited for parenteral delivery or as lead scaffolds for optimization and limit oral bioavailability. No PAINS or Brenk alerts were detected, all compounds satisfied Lipinski’s rule of five, and they lacked oral drug-likeness due to poor permeability. They are therefore best suited for parenteral delivery or as lead scaffolds for further optimization.