Thermoplastic elastomers (TPEs) exhibit a wide variation in viscosity and elasticity. A wide variation in morphology (i.e., copolymers, physical blends, and side-chain branched polymers) results in semi-Newtonian to highly shear-thinning behavior. In this study, a simple statistical design of experiments is used to optimize and characterize extrusion behavior of TPEs. Energy input to extrude and viscous dissipation are related to process parameters and polymer rheological characteristics using process physics based on fundamental mechanics of fluid flow of a polymer in a screw-barrel geometry. Metering zone temperature and rpm were observed to be the most significant parameters influencing melt temperature, extruder pressure, torque, and output. Extruder pressure and torque were lower for ultra-low-density polyethylene (ULDPE) than for Santoprene. Screw torque was linearly proportional to rpm for ULDPE, whereas it was nonlinear for Santoprene due to the high shear-thinning nature of Santoprene. Mechanical energy to extrude at the same rpm was higher for Santoprene than for ULDPE. Extruder efficiency, considering output per unit energy expended, was three times higher for ULDPE than for Santoprene.