In order to meet the mandated EPA2010 emissions for heavy duty commercial vehicle regulations, most applications require very large, complex, yet compact exhaust after-treatment systems. These systems not only contain the necessary substrates and filters to perform the proper emissions conversion, they also typically will consist of mixing pipes and internal reversing chambers all within very tight space proximity. Some of these systems are able to accomplish the complete emissions reduction and conversion within a single, large packaging unit. While there are advantages in fuel efficiency and perhaps overall packaging with these “single box” units, the disadvantage of these types of designs is that it prohibits many internal components from cooling down by the outside environment, which can pose thermal mechanical durability challenges. During Diesel Oxidation Catalyst (DOC) regeneration, also known as Diesel Particulate Filter (DPF) active regeneration, an additional amount of heat is released from DOC to DPF and spreads to the entire system in a very short period. This rapid heat generation results in a sharp temperature increase of the enclosed components and may cause components or system thermal fatigue failure in the long run. In this paper, a 3-D numerical model is developed to investigate this severe condition caused by DOC regeneration. The model incorporates the experimental data from the measurements in a diesel exhaust system developmental testing. With the well validated model, a transient conjugate heat transfer calculations is carried out using commercial computational fluid dynamic (CFD) software. The calculation starts from a steady state at normal operating condition towards a quasi-steady state for DOC regeneration. The system's responses such as the variation of surface temperature, flow uniformity, and pressure loss with time, are presented.