Purpose: Depression is a neurobiological disorder responsive to treatment with antidepressants. Some investigative research has indicated a negative correlation between the use of these drugs and failure of dental implant osseointegration. This study aimed to make an in vivo assessment of the impact of two antidepressants with distinct mechanisms of action on the osseointegration of dental implants, and their correlation with two different surface treatments. Materials and Methods: A total of 15 Rattus norvegicus albinus specimens received 4 titanium implants, 2 exhibiting a double acid-etched (DEA) surface, and 2 exhibiting a DEA surface coated in plasma-sprayed nanohydroxyapatite (NANO), distributed to the right and left tibias. The rats were randomly assigned to three groups: sertraline, amitriptyline, or saline, and received a daily oral dose of 5mg/kg, 5mg/kg, or 0.1ml, respectively, for 14 days prior to surgery, and for an additional 21 days thereafter until euthanasia. Removal torque (RT), bone-implant contact (BIC), and bone area (BA) were evaluated. Results: The findings indicated that both the removal torque and the BA percentage decreased in the groups administered antidepressants. The BIC percentage was similar among the groups when the NANO surface implant was used. Conclusions: It can be concluded that the antidepressants studied were associated with a higher possibility of osseointegration failure. Implants featuring NANO surface treatment could be used as an alternative in these instances to mitigate the negative impact of antidepressant therapy on bone repair.