I'm going to go against the grain and say that I think it is indeed possible, but not even remotely close to easy, probable, or worthwhile.
I'm a mechanical engineer by degree and trade, and I took every automotive / internal combustion class available during engineering school ~10 years ago. My final project in one of those classes was on modeling fuel economy.
When it comes to calculating fuel economy, there's literally only two factors: required horsepower and BSFC (brake specific fuel consumption).
Required horsepower is exactly that: the horsepower output needed from your motor to move your vehicle down the road. You'll need more horsepower for: a larger cross-sectional area, a higher coefficient of drag, higher rolling resistance tires (or drivetrain in general), higher speed, more weight (if going up / down hills), etc. And vice- versa for less horsepower.
BSFC is the exact amount of fuel that you burn to produce a horsepower; it's basically a measure of your engine's efficiency. It's mostly a factor of the overall architecture of the engine (size, number of cylinders, gas vs. diesel, head / cam design, etc.), but it does change somewhat depending on RPM, throttle position, vane position, etc. It can also be changed via tuning, but the gains here are generally speaking not that much, and they pretty much always come at the expense of increased emissions. I'll leave it up to you to decide if you care about that or not.
To calculate fuel consumption you simply multiple required horsepower by BSFC, and divide by your speed (and obviously some unit conversions in there as well). Fuel economy is basically the inverse of consumption, so to increase economy, you want to decrease required horsepower and BSFC. The equation also shows that you want to increase speed (which is obvious: you get better fuel mileage doing 20 mph than 0 mph), but the required horsepower goes up quickly as the aerodynamic drag starts going up, so there's a breakeven point, usually around 45-55 mph.
Many people, myself included, have seen occasional 20 mpg results from properly tuned trucks at reasonably interstate speeds / driving conditions; in my case, it's with a mostly stock, well-tuned 4x4 CCSB LB7, and I've done it fairly regularly at 65-70 mph highway-only drives. Using that as a starting point, you'll need to reduce BSFC and/or required horsepower to 67% of my current level to get to 30 mpg (20mpg / 67% = 30mpg goal), or more simply put: a 33% total improvement. What can you do that will help get to this goal?
1. Lower cross-sectional area. Not a lot you can do here, but putting smaller mirrors on, using skinnier tires / no offset outside fender, etc. will help. Lowering the truck will help a tiny bit. Total gains are probably 2-3% at best.
2. Reduced coefficient of drag. This is basically how streamlined the truck is. Again, lowering the truck, changing / removing mirrors, using wheels that are very flat / no pockets (think of the wheel covers you see on 18-wheelers), removing fender flares, building a front valance and/or streamlining the underbelly, taping off as much of the grill as possible, etc. This is where most of the gains will come. Should be able to get 10-15% improvement. Also, a RCLB will be better than a CCSB.
3. Reducing rolling resistance. Tires are the easiest way to do this, and should be good for a 1-2% improvement. 2WD will be better than 4WD, and a manual transmission superior to an automatic. 2WD and manual are probably good for another couple of percent over my truck.
4. Reducing weight. Weight makes 0 difference on a flat road at constant speed, but it does when accelerating or going up hills. There's nothing significant you can do here other than using a 2WD regular cab instead of a 4WD crew cab. But, that should be good for another couple percent. Removing the hitch and spare might save you 100 pounds, but that's not much in a 6000+ pound truck.
5. Slow down. This is a HUGE difference maker. It's hard to find the exact sweet spot without testing, but 50-55 mph usually is a marked improvement over 65-70 mph. I don't doubt for a bit that you could gain 10% by slowing down 10-15 mph from normal highway speeds.
6. Decrease BSFC. This is already mostly accounted for in my truck with the tune (it did pick up a solid 1-1.5 mpg over stock with the tune), but there's one other thing you can do: gear the truck up. Taller gears will reduce the rpm at a given speed, and with very few exceptions, lower rpm results in a lower BSFC. Probably not much, a few percent at most, but some. I'm not familiar with the gearing differences right offhand, but a ZF6 manual may have an advantage over the Allison here also.
Outside of those things, go read up on some of the hyper-miling techniques that can also significantly improve gas mileage. Things like driving-with-load, EOC (engine off coasting), etc. Those things really do work, but they also require active and deliberate input from the driver.
Add all those things up, and you get ~30%, very close to the 33% goal. So if you had a tuned, lowered, 2WD, RCLB, ZF6, with 3.42 gears, with stubby mirrors, good tires, some intermediate aerodynamic mods, and drove at steady 50-55 mph on the highway, could you get 30 mpg? Yea, I think so, at least occasionally. Mid-high 20s should come fairly regularly.
There used to be a guy, either on one of these diesel forums or maybe on the hypermiling forums, I forget, that had the exact truck I just described. I think his may have been a 6.0 Powerstroke (but a common rail Duramax should be just as good or better). And his lifetime average was 23-24 mpg over all types of driving. So if he can do low-mid 20s as an all-around average, I think doing high 20s-30 is certainly doable in some situations on the highway. You certainly won't do it every tank, as it doesn't take much stop-and-go or heavy acceleration to throw that average off.
All of that said, it's 10 times easier, usually cheaper, and way less of a headache to just get a beater. You'll spend a fair amount of money to do the above things, and it will likely take 50,00+ miles to pay back that difference. When you consider the increased maintenance cost of a diesel 3/4 truck vs. beater car, plus the fact that most beaters will easily do north of 30 mpg even at 75 mph highway speeds, you'll save more money with the car (and time, since you'll be doing 75 mph instead of 55). Not to mention, diesel (at least here in NC) is 30-40 cents a gallon more than gas. Seriously, go buy a nice, <100k mile 7th gen Honda Accord (4-cylinder) for $3000-$4000, and enjoy the peace and quiet driving down the highway at 75 mph getting 33 mpg.
