Purpose New-onset loss of olfaction and/or taste is now recognized among the hallmark symptoms of COVID-19. In most patients, these symptoms resolve completely and spontaneously within days. However, some patients experience persistent olfactory and gustatory dysfunction after COVID-19 resolution. We evaluated the efficacy of a treatment combining several therapeutic agents to target inflammation and endothelial dysfunction in patients with persistent hyposmia and dysgeusia. Methods This 12-month observational pilot study involved patients presenting with symptoms of hyposmia and dysgeusia 30 days after COVID-19 had subsided. The main objective was to evaluate the efficacy of a combination of systemic corticosteroids, a glycosaminoglycan (GAG)-based antithrombotic (mesoglycan), a diuretic, and a vitamin complex. The perceived extent of olfaction and taste impairment was assessed using an 11-point visual analog scale (VAS), where 0 = complete loss of olfaction/taste and 10 = complete recovery of olfaction/taste. Results Eighty-seven patients with post-COVID-19 hyposmia and dysgeusia were enrolled. At treatment start (T0), the mean VAS scores were 2.0 and 3.2 for olfactory and gustatory functions, respectively. Both functions appeared to improve progressively and significantly from T0 to 12 months. A shorter time between viral infection and the start of treatment was associated with a more pronounced recovery of both senses. Conclusions Combined systemic corticosteroid, GAG-based antithrombotic agent (mesoglycan), and diuretic may constitute an option for treating persistent hyposmia and dysgeusia associated with COVID-19. To ensure optimal recovery, early treatment start is recommended. The described treatment protocol deserves to be further evaluated.