Major depressive disorder is increasingly prevalent, and selective serotonin reuptake inhibitors (SSRIs) remain first-line pharmacotherapy. Beyond their canonical neuronal mechanism, attention has turned to potential off-target effects in peripheral tissues. Because serotonergic transport and receptor pathways have been described in vascular endothelial models, SSRIs could directly modulate vascular pathways. Thus, this study investigated the effects of 24-h exposure to selected SSRIs, including sertraline, fluoxetine, and paroxetine, on bioenergetics, redox status, extracellular purine handling, and endothelial activation markers in human microvascular endothelial cells (HMEC-1). SSRI exposure did not change total intracellular adenosine triphosphate (ATP), but consistently reduced adenosine diphosphate (ADP), resulting in higher ATP/ADP ratios and increased adenylate energy charge. Sertraline and fluoxetine reduced nicotinamide adenine dinucleotide (NADH) and basal reactive oxygen species (ROS) formation, whereas the NADH/NAD ratio was reduced after paroxetine and fluoxetine treatment. In the extracellular purine profiling, sertraline uniquely accelerated the degradation of ATP and adenosine monophosphate (AMP). Assessment of adhesion molecules by immunocytochemistry indicated divergent effects on endothelial activation markers, with fluoxetine decreasing intercellular adhesion molecule-1 (ICAM-1) and paroxetine increasing vascular cell adhesion molecule-1 (VCAM-1). Collectively, these findings suggest that SSRIs can modulate endothelial energy/redox balance and purinergic signaling in a compound-dependent manner and support further validation in primary and multicellular vascular models.