Background Long-term forms of depression, especially chronic and episodic, make it very hard for any individual to maintain a steady job or develop in his/her workplace, which reduces the ability to gain financial security. The purpose of this study is to investigate and thoroughly examine the impact of long-term depression on career trajectories and job stability using a methodical evaluation of the literature supplemented with case studies. Methodology This study combined a systematic review of available literature with a detailed case series analysis. The literature search was conducted systematically in three major databases, namely, PubMed, PsycINFO, and Scopus. The systematic review synthesized findings from studies that assessed the relationship between chronic and episodic long-term depression and employment-related outcome measures, i.e., job stability, upward career mobility, and socioeconomic status. The studies published between 2000 and 2024 were included and qualified. The case series contributed qualitative depth using eight personal experiences illustrating how the use of self-workplace dynamics interacted with depressive symptoms to shape employment. Results The systematic review provided consistent evidence that depression negatively influences employment status, such as decreased income and an increased rate of unemployment and disability claims. The current investigation included 29 studies, which were chosen after a rigorous screening process that included identifying 10,651 records and removing irrelevant or duplicate entries. The case series underlined further that it is the role of support executed by the workplace and societal stigma that mitigates or exaggerates these outcomes. In cases, people whose careers were disrupted by depression (job loss, low productivity, and long-term financial pressure) evidenced a huge change. Conclusions The effects of chronic and episodic long-term depression interfered with employment and socioeconomic well-being and, in fact, expanded beyond the individual to affect larger societal factors. Healthcare providers should collaborate with employers to ensure affected individuals receive appropriate accommodations in the workplace along with responses to mental health concerns. Further, policymakers should create inclusive policy environments to address the demands of people concerning job security and access to mental health related to depression. In addition, they should promote anti-stigma campaigns targeted at the reduction of societal and workplace discrimination against mental health issues.