The degree-day method is considered to be a fundamental and a rather simple method to estimate heating and cooling energy demand. This study aims in a detailed and accurate assessment of cooling and heating degree days in different locations within the Greater Athens area (GAA), Greece. To achieve this goal, hourly values of air temperature from eight different locations within the GAA, covering the period 2001–2005, were used. Thus, the monthly and the annual number of cooling and heating degree days for each one of the examined locations could be estimated separately. Furthermore, an effort is made to evaluate the energy consumption for a specific building, based on the degree-day method, to indicate the impact of the canopy layer urban heat island on neighboring regions within the GAA. Results reveal that there is great spatial variability of energy demand and energy consumption along with significant differences in expenses for heating and cooling among neighboring regions within the GAA. Finally, regarding the energy demands of buildings, it is important to take into account intra-urban variability of canopy layer climates against an ensemble mean throughout the city, because the latter can result in inaccurate estimations and conclusions.