To compare the systemic cytokines/chemokines levels over time during the evolution of children hospitalized with community-acquired pneumonia (CAP) with and without pneumococcal infection. Methods: Children less than 5‐years‐old hospitalized with CAP were prospectively investigated in Salvador, Brazil. Clinical data and biological samples were collected to investigate 20 etiological agents and to determine serum cytokines/chemokines levels on admission and 2 to 4 weeks later. Cases with pneumococcal infection received this diagnosis irrespective of also having other etiologies. Results: A total of 277 patients were enrolled, however, serum sample was unavailable for cytokine measurement upon admission (n = 61) or upon follow‐up visit (n = 36), etiology was undetected (n = 50) and one patient did not attend the follow‐up visit. Therefore, this study group comprised of 129 cases with established etiology. The median (interquartile range) age and sampling interval was 18 (9‐27) months and 18 (16‐21) days, respectively. Established etiology was viral (52.0%), viral‐bacterial (30.2%), and bacterial (17.8%). Pneumococcal infection was found in 31 (24.0%) patients. Overall, median interleukin‐6 (IL‐6; 10.6 [4.7‐30.6] vs 21.0 [20.2‐21.7]; P = .03), IL‐10 (3.5 [3.1‐4.5] vs 20.1 [19.8‐20.4]; P < .001), and CCL2 (19.3 [12.4‐23.2] vs 94.0 [67.2‐117.8]; P < .001) were significantly higher in convalescent serum samples, whereas median CXCL10 (83.6 [36.4‐182.9] vs 14.6 [0‐116.6]; P < .001) was lower. Acute vs convalescent levels evolution of IL‐10, CCL2, and CXCL10 did not differ among patients with or without pneumococcal infection. However, IL‐6 decreased (27.8 [12.3‐48.6] vs 20.8 [20.2‐22.6]; P = .1) in patients with pneumococcal infection and increased (9.0 [4.2‐22.6] vs 21.0 [20.2‐21.7]; P = .001) in patients without it. Conclusion: The marked increase of IL‐6 serum levels during the acute phase makes it a potential biomarker of pneumococcal infection among children with CAP.