Major depressive disorder (MDD) is a significant psychiatric condition, with many affected individuals not gaining remission from conventional treatments, leading to classification as treatment-resistant depression (TRD). This study aimed to investigate the potential of intravenous (IV) ketamine, particularly the S-enantiomer esketamine in nasal spray form, for treating patients with TRD and associated comorbidities. We report three cases of patients with diverse psychiatric and medical backgrounds whom all reported significant symptomatic relief from depressive episodes and suicidal ideation (SI) following esketamine administration. Additionally, esketamine seemed to proffer benefits beyond the primary depressive symptoms, positively impacting other comorbid conditions, such as agitation, self-injurious behavior (SIB), and chronic pain. The goal of this paper is to highlight that while esketamine's primary utility is in addressing TRD, its therapeutic potential may extend to a variety of associated conditions. However, it is crucial to underscore the heterogeneity of MDD, emphasizing the necessity for individualized therapeutic approaches and further research into esketamine's broader applications.