This meta-analysis looked at the role of circulating pneumo proteins in the detection, severity, and prognosis of COVID-19. The researchers combed through five database systems and a variety of other sources up until December 16, 2021. The final results were presented as a standardized mean difference (SMD) and a 95% CI. The pooled analysis was performed using RevMan 5.3, Stata 16, and Meta-DiSc 1.4. A total of 2,432 participants were included from 26 research groups. Patients with COVID-19 had higher circulating KL-6, SP-D, and SP-A levels (SMD 1.34, 95% CI [0.60, 2.08]; SMD 1.74, 95% CI [0.64, 2.84]; SMD 3.42, 95% CI [1.31, 5.53], respectively) than healthy individuals. Neither survivors nor non-survivors had substantially different levels of SP-D in their blood (SMD -0.19, 95% CI [-0.78, 0.40]). Circulating KL-6, SP-D, and RAGE levels in patients with mild to moderate COVID-19 were significantly lower (SMD − 0.93, 95% CI [−1.22, −0.65]; SMD −1.32, 95% CI [−2.34, −0.29]; SMD −1.17, 95% CI [−2.06, −0.28], respectively) than in patients with severe COVID-19. Subgroup analysis of SP-D in patients with mild to moderate versus severe COVID-19 revealed that country and total number may be associated with heterogeneity. KL-6 for severity, KL-6 for mortality, and SP-D for severity were all shown to have limited diagnostic usefulness in a meta-analysis evaluating diagnostic accuracy. So, the diagnosis, severity, and prognosis of COVID-19 can be deduced from the levels of circulating pneumo proteins (KL-6, SP-D, and RAGEs), and further investigations are warranted.