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Twenty-four analogs based on triazinoindole bearing benzimidazole/benzoxazole moieties (<b>1</b>–<b>25</b>) were synthesized. Utilizing a variety of spectroscopic methods, including ¹H-, ¹³C-NMR, and HREI-MS, the newly afforded compounds (<b>1</b>–<b>25</b>) were analyzed. The synthesized analogs were tested against urease enzyme (in vitro) as compared to the standard thiourea drug. All triazinoindole-based benzimidazole/benzoxazole analogs (<b>1</b>–<b>25</b>) exhibited moderate to excellent inhibition profiles, having IC₅₀ values of 0.20 ± 0.01 to 36.20 ± 0.70 μM when evaluated under the positive control of thiourea as a standard drug. To better understand the structure–activity relationship, the synthesized compounds were split into two groups, “A” and “B.” Among category “A” analogs, analogs <b>8</b> (bearing tri-hydroxy substitutions at the 2,4,6-position of aryl ring C) and <b>5</b> (bearing di-hydroxy substitutions at the 3,4-position of aryl ring C) emerged as the most potent inhibitors of urease enzyme and displayed many times more potency than a standard thiourea drug. Besides that, analog <b>22</b> (which holds di-hydroxy substitutions at the 2,3-position of the aryl ring) and analog <b>23</b> (bearing <i>ortho</i>-fluoro substitution) showed ten-fold-enhanced inhibitory potential compared to standard thiourea among category “B” analogs. Molecular docking studies on the active analogs of each category were performed; the results obtained revealed that the presence of hydroxy and fluoro-substitutions on different positions of aryl ring C play a pivotal role in binding interactions with the active site of the targeted urease enzyme.