Threatening experiences can lead to traumatic memories and cause post-traumatic stress disorder (PTSD). Under certain conditions, the retrieval of a stable consolidated memory destabilizes it triggering an active re-stabilization process called reconsolidation. During this unstable phase, memory can be vulnerable to interference by several pharmacological agents. In this work, we evaluate in mice whether a single dose of the antidepressant fluoxetine (Flx, 10 mg/kg i.p.) can disrupt contextual fear memory by blocking reconsolidation. First, we administered Flx after a brief exposure (3 min) to the training context (reactivation procedure) and measured freezing behavior when mice were re-exposed to the training environment one day later. Second, we investigated the effect of Flx administered 6 hours after reactivation or in its absence and found no effect on freezing behavior compared with vehicle injection. Flx-induced amnesia lasted for at least 3 weeks after training. We found no difference in the effect of Flx between male and female mice. Our findings indicate that a single systemic dose of Flx selectively disrupts the reconsolidation of a contextual fear memory. Given that current PTSD treatments involve long and emotionally exhausting procedures, blocking the reconsolidation of traumatic memories by a single dose of an antidepressant could be a starting point for developing a promising short and effective treatment for PTSD.