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In this study, we introduce an application of a Cellular Automata (CA)-based system for monitoring and estimating the spread of epidemics in real world, considering the example of a Greek city. The proposed system combines cellular structure and graph representation to approach the connections among the area's parts more realistically. The original design of the model is attributed to a classical SIR (Susceptible–Infected–Recovered) mathematical model. Aiming to upgrade the application's effectiveness, we have enriched the model with parameters that advances its functionality to become self-adjusting and more efficient of approaching real situations. Thus, disease-related parameters have been introduced, while human interventions such as vaccination have been represented in algorithmic manner. The model incorporates actual geographical data (GIS, geographic information system) to upgrade its response. A methodology that allows the representation of any area with given population distribution and geographical data in a graph associated with the corresponding CA model for epidemic simulation has been developed. To validate the efficient operation of the proposed model and methodology of data display, the city of Eleftheroupoli, in Eastern Macedonia—Thrace, Greece, was selected as a testing platform (Eleftheroupoli, Kavala). Tests have been performed at both macroscopic and microscopic levels, and the results confirmed the successful operation of the system and verified the correctness of the proposed methodology. [ABSTRACT FROM AUTHOR]