This study analyzes the road freight sector of São Paulo state to identify the best options to reduce greenhouse gases emissions and local pollutants, such as particulate matter, nitrogen oxides, carbon monoxide, and hydrocarbons. Additionally, the investment cost of each vehicle is also analyzed. Results show that electric options, including hybrid, battery, and hydrogen fuel-cell electric vehicles represent the best options to reduce pollutants and greenhouse gases emissions concomitantly, but considerable barriers for their deployment are still in place. With little long-term planning on the state level, electrification of the transport system, in combination with increased renewable electricity generation, would require considerable financial support to achieve the desired emissions reductions without increasing energy insecurity.