We aimed to model tau abnormalities in the early and advanced stages of Alzheimer’s disease and other tauopathies. By doing so, we wanted to evaluate molecules capable of preventing tau-mediated neurodegeneration. To achieve this, we established cultures of mouse cortical neurons in which hyperphosphorylated (but not aggregated) tau accumulates in a significant population of neurons following chronic exposure to redox-active iron from hemin (Hm), a breakdown product of hemoglobin. Using experimental conditions in which p-tau (AT8 immunosignal) accumulation occurs without concomitant neuronal loss, we found that the end-product of purine metabolism, uric acid (UA), but neither its immediate precursor xanthine nor its oxidized product allantoin prevents p-tau build-up. Imaging studies with the fluorogenic probe DHR-123 revealed that UA reduced p-tau load by inhibiting iron-dependent lipid peroxidation. Like UA, doxycycline (DOX) and a non-antibiotic derivative of oxytetracycline chemically referred to as 12a-deoxy-dedimethylamino-oxytetracycline (DOT) efficiently restrained p-tau accumulation and oxidative stress induced by Hm. Interestingly, UA and DOT (but not DOX) retained their capacity to prevent p-tau build-up when tau neurodegenerative changes were due to low-intensity excitotoxic-oxidative insults elicited by glutamate. Finally, using a thioflavin-T assay and 2N4R tau monomers to model tau aggregation at a later disease stage, we found that UA, DOT, and DOX restrained the formation of tau fibrils with the following order of potency: DOT>DOX>UA. Altogether, present results suggest that UA elevating agents and the non-antibiotic tetracycline DOT could have therapeutical utility to prevent tau-related abnormalities.