Inhibiting the facial expression of negative emotions via botulinum toxin A (BTX) has been shown to mitigate symptoms of clinical depression in randomized controlled trials. This retrospective case study sought to reproduce the beneficial effects of BTX in a naturalistic setting for major depressive disorder and collect casuistic data on its effect on other mental disorders. Moreover, we describe symptom development across multiple treatment cycles with BTX, and assess the implementation of additional injection targets in the lower face region. Participants were N = 51 adult psychiatric outpatients mainly seeking treatment for depression. Over 50% suffered from comorbid psychiatric conditions, predominantly generalized anxiety disorder (GAD) or borderline personality disorder (BPD). A pre–post case series design was adapted. All participants received BTX-injections in the glabellar region on at least one occasion. Some received additional injections in the mouth region and over multiple treatment cycles. Treatment response was followed up by self-rated scales at varying time intervals post treatment. The results showed that BTX may yield favorable outcomes across multiple and comorbid mental disorders, especially, however, for patients suffering from depression. It potentially prevents the recurrence of clinical symptoms if applied regularly. Adding additional regions of the face does not seem to be superior over applying it to the glabellar region alone. The results add to the growing evidence that BTX therapy is effective in alleviating symptoms of depression. Positive effects can be sustained and reinstated, when applied over multiple treatment cycles. Observed symptom reduction in other psychiatric disorders was less pronounced. Further research is needed to understand the mechanisms by which BTX therapy reduces psychiatric symptoms.