Background: Depression and anxiety have been correlated with elevated risks for quality-of-life (QOL), adverse outcomes, and medical expenditure in patients with acute coronary syndrome (ACS). However, the relevant data are lacking for Chinese ACS populations, especially regarding different effects of major depression, anxiety, and comorbidity. The objective of this study was to evaluate the dynamic changes of depression and/or anxiety over 12 months and examine the effects of depression, anxiety, and comorbidity on QOL, adverse outcomes, and medical expenditure in Chinese patients with ACS. Methods: For this prospective longitudinal study, a total of 647 patients with ACS were recruited from North China between January 2013 and June 2015. Among them, 531 patients (82.1%) completed 12-month follow-ups. Logistic regression model was utilized for analyzing the association of baseline major depression, anxiety, and comorbidity with 12-month all-cause mortality, cardiovascular events, QOL, and health expenditure. Results: During a follow-up period of 12 months, 7.3% experienced non-fatal myocardial infarction (MI) and 35.8% cardiac rehospitalization. Baseline comorbidity, rather than major depression/anxiety, strongly predicted poor 12-month QOL as measured by short-form health survey-12 (odds ratio [OR]: 1.77, 95% confidence interval [CI]: 1.22-2.52, P = 0.003). Regarding 12-month non-fatal MI and cardiac re-hospitalization, baseline anxiety (OR: 2.83, 95% CI: 1.33-5.89, P < 0.01; OR: 4.47, 95% CI: 1.50-13.00, P < 0.01), major depression (OR: 2.58, 95% CI: 1.02-6.15, P < 0.05; OR: 5.22, 95% CI: 1.42-17.57, P < 0.03), and comorbidity (OR: 6.33, 95% CI: 2.96-13.79, P < 0.0001, OR: 14.08, 95% CI: 4.99-41.66, P < 0.0001) were all independent predictors, and comorbidity had the highest predictive value. Number of re-hospitalization stay, admission frequency within 12 months and medical expenditure within 2 months were the highest in patients with ACS with comorbidity. Conclusions: Major depression and anxiety may predict 12-month non-fatal MI and cardiac re-hospitalization. However, comorbidity has the highest predictive value with greater medical expenditure and worse QOL in Chinese patients with ACS. And depression with comorbid anxiety may be a new target of mood status in patients with ACS.