Challenges such as long-term cultivation and sludge floatation are common in flocculent sulfide-oxidizing autotrophic denitrification (SOAD) systems. The present study aims to optimize the granulation of SOAD sludge by mainly adjusting the reactor configuration and mixing mode. Three liquid-lift upflow reactors viz. a reactor equipped with a three-phase separator (Reactor A), a modified version of Reactor A equipped with a hydraulic regulator (Reactor B), and a reactor with a mounted baffle and intermittent mechanical mixing (Reactor C). These reactors were operated for more than 160 days. The results showed that dense and compact granules with 200 μm of diameter developed within 40 days and gradually increased to approximately 400 μm in Reactor C, which had a volatile suspended solids (VSS) concentration of 7500 mg VSS/L of sludge concentration; this Reactor C was also subject to modified reactor configuration and operating conditions. In comparison, filamentous granules formed in Reactor A due to a low substrate loading and granules formed in Reactor B but with significant biomass loss caused by sludge flotation. Both of the reactors only have ≤1000 mg VSS/L VS 7500 mg VSS/L in Reactor C. Also, Reactor C having 0.77 h of hydraulic retention time (HRT) and 0.94 kgNO-N/m d & 1.87 kgS-S/m d of nitrogen and sulfide loading rate, respectively, showed a better performance in terms of nitrate removal (89%) and sulfur conversion (above 70%) due to its enrichment by the typical autotrophic denitrifiers (39.0% of Thiobacillus, 22.4% of Sulfurimonas) in the granules. Our findings provide a method to optimize the design and operation of granulation reactors that can be extended to similar processes treating organic-deficient wastewaters.