Question Is impaired mood homeostasis (ie, failure to stabilize mood via mood-modifying activities) associated with low mood and a history of depression? Findings In 2 case-control studies including a total of 58x202f;328 participants from low-, middle-, and high-income countries, mood homeostasis was lower in participants with low mood and those with a history of depression. Dynamic simulations showed that impaired mood homeostasis may lead to increased incidence and longer duration of depressive episodes. Meaning Mood homeostasis may be a new target for the development of novel treatments and the optimization of existing ones such as activity scheduling. Importance Existing therapeutic options are insufficient to tackle the disease burden of depression, and new treatments are sorely needed. Defining new psychotherapeutic targets is challenging given the paucity of coherent mechanistic explanations for depression. Objective To assess whether mood homeostasis (ie, the stabilization of one's mood by engaging in mood-modifying activities) is a possible new therapeutic target by testing the hypothesis that people with low (vs high) mean mood and people with (vs without) a history of depression have impaired mood homeostasis. Design, Setting, and Participants The quantitative association between mood and daily activities was computed in 2 large case-control studies based on the 58sec data set (collected from December 1, 2012, to May 31, 2014, and analyzed from April 1 to 30, 2019), and the World Health Organization Study on Global Aging and Adult Health (WHO SAGE) data set (collected from January 1, 2007, to December 31, 2010, and analyzed from June 1 to 30, 2019). The 58sec data set consists of self-enrolled participants from high-income countries. The WHO SAGE data set consists of nationally representative participants in low- and middle-income countries recruited via cluster sampling. Main Outcomes and Measures The main outcome (defined before data analysis) was the difference in mood homeostasis between people with high vs low mean mood (58sec data) and between people with vs without a history of depression (WHO SAGE data). Results A total of 28x202f;212 participants from the 58sec data set (65.8% female; mean [SD] age, 28.1 [9.0] years) and 30x202f;116 from the WHO SAGE data set (57.0% female; mean [SD] age, 57.8 [14.7] years) were included, for an overall study population of 58 328 participants. Mood homeostasis was significantly lower in people with low (vs high) mean mood (0.63 [95% CI, 0.45 to 0.79] vs 0.96 [95% CI, 0.96 to 0.98]; P < .001) and in people with (vs without) a history of depression (0.03 [95% CI, -0.26 to 0.24] vs 0.68 [95% CI, 0.55 to 0.75]; P < .001). In dynamic simulations, lower mood homeostasis led to more depressive episodes (11.8% vs 3.8% yearly risk; P < .001) that lasted longer (4.19 vs 2.90 weeks; P = .006). Conclusions and Relevance In this study, mood homeostasis appeared to have been impaired in people with low mood and in those with a history of depression. Mood homeostasis may therefore provide new insights to guide the development of treatments for depression. These case-control studies assess whether mood homeostasis is a possible new therapeutic target by testing the hypothesis that people with low (vs high) mean mood and people with (vs without) a history of depression have impaired mood homeostasis.