Evidence from several studies indicates that the long-term treatment of selective serotonin reuptake inhibitors (SSRIs) is associated with a decrease in bone mass and increase the risk of fractures. The present work evaluated and compared the effect of treatment with two SSRIs viz. fluoxetine and escitalopram on bone biomarkers (P1NP and βCTX) in male Wistar rats. In addition, the effect of these drugs on bone microarchitecture of lumbar and tibia bones was carried out. Fluoxetine (8.2 mg/kg) treatment for 40 days significantly reduced (P < 0.01) the levels of the P1NP while escitalopram (2.0 mg/kg) was without such effects. Both drugs were devoid of any effects on bone resorption marker βCTX. The pCREB levels were reduced by both the antidepressants but the reduction was significantly (P < 0.001) marked in case of fluoxetine. The micro-CT data revealed that fluoxetine, but not escitalopram, treatment resulted in reduced bone volume fraction, trabecular thickness and number while increased trabecular separation, trabecular pattern factor and connectivity density in the proximal tibial metaphysis. No significant changes were, however, discernible in lumbar bones. The study shows that fluoxetine reduces bone formation possibly through reduced pCREB mediated by the action of gut serotonin in osteoblasts and that escitalopram can be a better treatment option as far as adverse effects on bone are concerned.