Alginate is a biopolymer used in numerous biomedical applications. The current work describes the purification of alginate from Sargassum horneri and method optimization for formulating drug-loaded microparticles by water-in-oil emulsification/internal gelation. Molecular weights of S. horneri alginate were ranging 50–70 kDa. Among 16 method optimizations, the F4 method was selected for further studies based on shape descriptor parameters which indicated, 0.24 ± 0.01 circularity, 0.80 ± 0.11 roundness, 1.27 ± 0.20 aspect ratio between long and short axis, and less aggregation in PBS. Processing parameters of the F4 method were; CaCO3/alginate ratio of 20/1 (w/w), 5% span 80 in oil (v/v), water/oil phase ratio of 1/20 (v/v), and 1000 rpm emulsification speed. Hollow pores were visible on the surface of dehydrated F4 microparticles. F4 microparticles indicated 41.84 ± 2.93 and 45.86 ± 1.65% encapsulation efficiencies for phloroglucinol (F4P) and indomethacin (F4I) with 32.69 ± 1.35 and 31.69 ± 1.98% loading capacities. These microparticles were found to be desirable for extending drug release over short periods (0–3 days) under pH 2.0–7.4. F4P and F4I were effective in suppressing intracellular reactive oxygen species in FD exposed HaCaT cells while increasing cell viability over 24 - 48 h duration.