We performed a retrospective, case-control study in consecutive ischemic stroke patients admitted to our stroke rehabilitation unit. Patients were matched for severity of neurological impairment (evaluated with the Canadian Neurological Scale, CNS), age (difference within 1 year), and onset admission interval (difference within 3 days). Participants were divided into two subgroups according to the presence or absence of PSD. Aim was to assess the specific influence of post-stroke depression (PSD) and antidepressant treatment on both basal functional status and rehabilitation outcomes. All PSD patients were treated primarily with serotoninergic antidepressants (AD). The final sample included 280 patients with depression (out of 320 found in a whole case series of 993 ischemic patients, i.e., 32.25%) and 280 without depression. Forty patients with depression were excluded because they had a history of severe psychiatric illness or aphasia, with a severe comprehension deficit. On one hand, PSD patients obtained lower Barthel Index (BI) and Rivermead Mobility Index (RMI) scores at both admission and discharge, with minor effectiveness of rehabilitative treatment and longer length of stay; on the other hand, this group had a lower percentage of dropouts. Lastly, PSD patients showed a different functional outcome, based on their response to antidepressant therapy, that was significantly better in responders than in non-responders (13.13%). Our results confirm the unfavorable influence of PSD on functional outcome, despite pharmacological treatment.