The Interstate highways are designed to carry interstate commercial truck traffic through large cities. If you must go through, I don't think you can find a better route than what the big trucks use.
However, I like to avoid big cities by 50 to 100 miles, if I can, not so much because of the cities but because of the universally bad driving behavior I encounter on suburban freeways or expressways. For example, I've worked out a number of routes between NE Oklahoma and southern Michigan where the largest city I must go through is Springfield, Illinois, though the fastest routes might take me through Saint Louis, Kansas City, Indianapolis, or across the south edge of Chicago.
If I must go through, I figure out which lanes the big trucks are using, and blend in with them.