Electrification of heavy-duty vehicles (HDVs) used for passengers and goods transportation is a key strategy to reduce the high levels of air pollution in large urban centers. However, the high investment cost of the commercially available electrified HDVs has limited their adoption. We hypothesized that there are applications where the operation with tailored electrified HDVs results in a lower total cost of ownership and lower well-to-wheel emissions of air pollutants, with higher acceleration capacity and energy efficiency than the fossil-fueled counterparts. The road transportation services running on fixed routes with short span distances (<50 km), such as the last mile cargo distribution and the passenger shuttle services, is a clear example with a high possibility of cost reduction through tailored electric HDVs. In this work, we present a methodology to define the most appropriate configuration of the powertrain of an electric vehicle for any given application. As a case study, this work aimed to define an electric powertrain configuration tailored for a university shuttle service application. A multi-objective weighted-sum optimization was performed to define the best geometrical gearbox ratios, energy management strategy, size of the motor, and batteries required. Based on three different driving profiles and five battery technologies, the results showed that, based on a 50 km autonomy, the obtained powertrain configuration satisfies the current vehicle operation with a reduced cost in every driving profile and battery technology compared. Furthermore, by using lithium-based batteries, the vehicle’s acceleration capacity is improved by 33% while reducing energy consumption by 37%, CO2 emissions by 31%, and the total cost of ownership by 29% when compared to the current diesel-fueled buses.