Historical trends indicate that different cultures across Africa attach different meanings to mental health illness. Ugandan cultures, as with their understanding of other family calamities such as death, barrenness, and most misfortunes, largely root mental illness in the concepts of the spirit world, supernatural possession, the role of the living dead, witchcraft and divination, and the cosmic world of personhood. Such perceptions continue to prevail despite reports of increasing prevalence of mental health conditions in Uganda compared to other low-income countries. Vulnerability incidences to mental health and emotional well-being have been a concern in Uganda’s health policy reforms for decades. Recent concerns about increasing cases of mental health and loss of serenity in the Ugandan populace as reported by the Ministry of Health are mainly attributed to the stigma, anxiety, and socioeconomic distress associated with the COVID-19 pandemic. While causes of mental health have received enormous attention, little has been done to ascertain the meanings and interpretations the local communities confer to mental illness. As argued by this chapter, local perceptions hugely influence how mental illness is explained and the decisions and responses to managing the illness, including health seeking behaviors. In view of the concept of personhood, as is embedded in the three distinctive forms of agency—the self, spiritual, and social—the paper documents how mental illness is locally constructed in Uganda and provides useful data in understanding lay conceptualizations. It recommends recognizing alternative modes of treatment in addition to medical diagnostics.