Homelessness is an extreme form of poverty and deprivation and a major public health issue. The purpose of this study was to examine the quality of life and coping strategies among homeless people in Greece, in relation to depression and posttraumatic stress disorder. The research sample included 64 homeless people, of which 76.2% were men, mostly aged 45–66 years (58.1%), who had requested their inclusion in a social reintegration program implemented in three municipalities of the wider metropolitan area of Athens. Participants completed five questionnaires: demographic data, quality of life assessment (WHOQOL-26), symptoms of posttraumatic stress disorder (PCL-5), emotional states of depression, anxiety, and stress (DASS-21), and measures of coping strategies (Brief COPE). The results showed that the sample had a low quality of life, while a significant proportion of these people had severe to extremely severe levels of depression, anxiety, and stress, and a high prevalence of post-traumatic stress disorder (PTSD). It was also shown that the use of maladaptive coping strategies is significantly associated with high levels of depression, anxiety, and stress; moreover, PTSD is strongly linked to depression, while the high levels of depression, anxiety, and stress among the homeless are strongly related to reduced quality of life. Posttraumatic stress disorder, depression, and maladaptive coping strategies often used by homeless people can negatively affect their quality of life and complicate psychosocial rehabilitation efforts. Therefore, recovery and enhancement of their quality of life imply a multidimensional and holistic approach to assessing and focusing on their personalized needs.