Background Centri-lobular nodules are the most common pattern of diffuse pulmonary nodules encountered on high-resolution computed tomography (HRCT). HRCT with post-processing techniques such as obtaining maximum intensity projection (MIP) is helpful in making centri-lobular nodules more conspicuous. The study aimed to highlight the role of HRCT with its reconstruction capabilities in the detection and characterization of centri-lobular pulmonary nodules, interpret the most frequent associated findings, and correlate with the clinical findings to reach the most appropriate diagnosis. Results The study included 58 patients; 41.4% males and 58.6% females. Their age ranged from 2 to 67 years with mean age of 25.69. The centri-lobular nodules numbers, distribution, shape, and associated HRCT chest findings were identified. The top three etiological diagnoses were infection/inflammation in 50.0% of cases followed by acute viral bronchiolitis in 27.6% and inhalation bronchiolitis in 19.0% of cases. Correlation of HRCT findings with the clinical diagnosis was carried out with consequent formulation of an algorithm for the diagnostic approach of various etiologies of centri-lobular pulmonary nodules. Conclusions HRCT is a useful tool in the detection and characterization of centri-lobular pulmonary nodules. It can be used to differentiate the different etiologies that share centri-lobular nodularity. Other associated features and multidisciplinary approach are essential for further characterization of the most relevant etiological diagnosis.