Mesencephalic astrocyte-derived neurotrophic factor (MANF), a novel endoplasmic reticulum stress-induced neurotrophic factor, exerts a protective role in both nervous and non-nervous systems. However, the relationship between serum MANF content and community-acquired pneumonia (CAP) patients remains unclear. A total of 319 adult patients diagnosed with CAP were enrolled. Serum MANF level was quantified using enzyme-linked immunosorbent assay (ELISA). A prospective cohort study was conducted to investigate the association of serum MANF levels with severity and prognosis. Compared with healthy volunteers, serum MANF content was evidently upregulated in CAP patients. The level of serum MANF was dramatically increased in parallel with the scores of CURB-65, PSI, APACHE II, and SMART-COP in CAP cases. Additionally, multivariate linear and logistic regression analyses revealed that serum MANF level was positively associated with scoring criteria among CAP patients. Besides, serum MANF level on admission was significantly elevated in CAP patients who required mechanical ventilation, ICU admission, and died within 30 days. Moreover, the higher serum MANF level on admission evidently increased the risk of poor prognosis during hospitalization. There was a better predictive power of serum MANF for poorly prognostic outcomes in CAP patients. The expression of serum MANF exhibits the positive correlations with the severity and poor prognosis among CAP patients. Serum MANF may have considerable clinical value and be regarded as a diagnostic and prognostic biomarker for CAP.