Topical fungal infections including, Tinea capitis with escalating resistance to conventional therapies are a rising concern globally. Studies have shown substantial in vitro efficacy of plant compounds against fungal pathogens. This study utilized flavonoid glycosides from Dicerocaryum senecioides and Diospyros mespiliformis as active compounds to formulate a topical cream against Tinea capitis. The in vitro test utilized disc diffusion assay prepared from fungal isolates obtained from individuals showing resistance to topical miconazole. Clinical trials were performed using volunteers. Both isolated strains exhibited substantial in vitro susceptibility to the cream formulation with inhibition zones ranging between 10 and 18 mm. MIC values for both test organisms ranged between 85 mg/ml and 120 mg/ml. The cream showed stability both physico-chemically and against microbial contamination. Physicochemical parameters evaluated include colour, pH, appearance, particle size, phase separation, phase inversion, creaming, spread-ability, electrical conductivity and in vitro occlusivity test and were within the accepted range. In limited clinical trials using volunteers, Tinea capitis started disappearing as from day 5 by topically applying the cream twice per day. All the patients were completely healed by the 7th day. The results of the study showed that flavonoid glycosides from D. senecioides and D. mespiliformis are good candidates to be utilized as active natural compounds against Tinea capitis resistant strains. Therefore more clinical trials and structural elucidations are recommended.