Background: Acne vulgaris (AV) is a common inflammatory skin disease involving dysfunction of the pilosebaceous unit. Many mechanisms for the pathogenesis of acne have been postulated. However, the precise pathogenesis is still uncertain. Objective: This study aimed to measure serum calprotectin levels in AV and to correlate its level with the activity and severity of the disease. Patients and methods: A total of 80 subjects were subdivided into two groups; group I included 40 patients complaining of AV with different severity levels, and group II had 40 healthy age and sex‐matched participants as a control group. Serum calprotectin level was measured in both groups by the enzyme‐linked immunosorbent assay (ELISA) method. Results: Serum calprotectin concentration was statistically significantly (p=0.0001) higher in the patient group when compared to the controls. There was a statistically significant (p = 0.001) difference among subgroups of patients according to disease severity regarding serum calprotectin concentration. There was a high-significant positive correlation between serum calprotectin concentration and disease severity. Calprotectin concentration could be used to diagnose AV with cutoff points higher than 1.03 ng/ml (with 77.5% sensitivity, 80% specificity) and also can detect its severity with cutoff points higher than 1.1 ng/ml with 96.3% sensitivity, 100% specificity to differentiate the mild cases from moderate and severe ones. Conclusion: Serum calprotectin concentration represents a valuable tool for diagnosing the inflammatory nature and monitoring the disease activity in AV patients.