Neurodegenerative disease is one of the greatest health crises in the world and as life expectancy rises, the number of people affected will continue to increase. The most common neurodegenerative disease, Alzheimer's disease, is a tauopathy, characterized by the presence of aggregated tau, namely in the form of neurofibrillary tangles. Historically, neurofibrillary tangles have been considered the main tau species of interest in Alzheimer's disease; however, we and others have shown that tau oligomers may be the most toxic form and the species responsible for the spread of pathology. We developed a novel anti-tau oligomer-specific mouse monoclonal antibody (TOMA) and investigated the potential of anti-tau oligomer passive immunization in preventing the toxicity of tau pathology in Htau mice. We injected pure brain-derived tau oligomers intracerebrally in 3-month-old wild-type and Htau mice and investigated the protective effects of a single 60 μg TOMA injection when compared to the same dose of non-specific IgG and found that TOMA conferred protection against the accumulation of tau oligomers and cognitive deficits for up to 1 month after treatment. Additionally, we injected pure brain-derived tau oligomers intracerebrally in 3-month-old wild-type and Htau mice and treated animals with biweekly injections of 60 μg TOMA or non-specific IgG. We found that long-term administration of TOMA was effective as a preventative therapy, inhibiting oligomeric tau and preserving memory function. These results support the critical role of oligomeric tau in disease progression and validate tau oligomers as a potential drug target.