The Spirit is a movement that entails the five dimensions of the Human being—intellectual, physical, social, emotional, and spiritual. Spiritual distress (SD) and depression are related to spirituality and are most prevalent in palliative care (PC) settings. SD and depression have a deep connection to the inner energy of the Human being. Both can affect and be affected by all the five dimensions of the Human being and negatively impact the quality of these patients’ lives. Men seek meaning in life (MIL), and a lack of this dimension is common in SD and depression. Nevertheless, although closely interrelated, SD and depression are distinct diagnoses. There seems to be evidence of having precise clinical indicators and different pharmacological and non-pharmacological therapeutic approaches. Patient-centred approaches should be the gold standard practice at this particularly vulnerable moment.