Where does gas mileage go?

Your RX300 is doing the best it can with what it has. Some reasons why:

The 2002 RX300 has a coefficient of drag of 0.36. The 2013 GX460 has a coefficient of drag of 0.35. The GX460 looks boxier, but it's experiencing similar air resistance.

The RX300 has a 4 speed transmission. The GX460 has a 6 speed. This gives the GX460 (at least) two overdrive gears while leaving other gears optimized for performance.

The RX300 makes 200 HP at 5800 RPM and 222 lb-ft at 4400 RPM. The GX460 makes 301 HP at 5500 RPM and 329 lb-ft at 3500 RPM. More torque, at a lower RPM, lets the overdrive gears be more aggressive, letting the engine run at lower RPM and use less fuel.

The GX460 does weigh more, but this is likely outweighed by the other factors. Also, weight is less of an issue at highway speeds on relatively level ground.

The GX460's 1UR-FE V-8 is not direct injection. The 1UR-FSE it was derived from has direct injection.

The other comments are also valid: newer engine technology may make the 460 engine more efficient in other ways.

The bigger engine makes more torque down low, so it's better optimized for highway cruising when in the proper gear. Weight makes less difference at highway speeds, as wind drag is the biggest factor. Both your rigs are big boxy SUVs and so the aero probably isn't much different. Hence the torquier engine being more efficient on the highway.

This is why Corvettes can get 30mpg and still have 500hp engines. They make the same torque at low cruising RPMs as they do at higher RPMs. The engine just lumbers along at low speed, while a smaller displacement engine is going to be working harder to break through the wind.

As others have already mentioned, the transmission gearing makes a huge difference. In addition to gears, technology and frontal drag coefficient, peak engine efficiency to generate enough HP for steady state cruising speed will also vary.

https://www.youtube.com/watch?v=s-aK-GDp2tA - this is an exaggerated example of how loading an engine 50% vs 90% can impact real world fuel economy.

I'd bet the older car would beenfit from things like new plugs, fuel system cleaning, full lube and such. It's got 10 years more wear, more time for all those bearings to build up friction, etc; but what you describe sounds like more than just age and like you may have some problems.

Does it act like it has transmission problems? an automatic can be subtle about its issues until its suddenly not.

Fuel efficiency is a matter of fine tuning. Just making a car smaller and having a smaller engine doesn’t always mean you get better fuel efficiency.

For instance there are many small if not outright tiny cars that have much worse fuel efficiency than the Toyota Corolla. The Corolla is carefully designed in every respect, cars like the Mini Cooper make ‘German Engineering’ look shoddy.

My guess is the biggest factor would be engine technology and transmission. I'm not familiar with those vehicles, but as an example, if the transmission in the rx300 is 6 gears and the one in the gx460 is 8 gears, that would be a big difference. It could also be that the newer one is using direct injection or variable valve timing while the older one is not.

My guess is the 460 has direct injection fuel system which allows for higher compression from charge cooling so more efficiency (~8%?).

Bigger and heavier takes more energy. That's straight out physics.

Both of the cars mentioned are big and heavy and non-aerodynamic. (I'd even call the RX300 'boxy'.) If you want something with efficient MPG, you want something small, light and aerodynamic. You don't mention the transmission, so I assume they're both automatics. If you want good MPG you throw away the automatic and use a manual.

As regards the RX300 being not so great, it's old, you've worn down the engine and transmission and wheel-bearings, and the electronics are not as advanced as today's. I'm too lazy to look, but what are the figures for fuel-octane rating and compression-ratios? Would those also have a bearing on the question?

Efficiency. An ice has inevitable losses and avoidable such. Ten years seem have been enough for the engineers to find how they can avoid some of the mechanic losses between the combustion and the actual mechanical movement.

On the highway, the main two issues are aerodynamic drag and drivetrain efficiency.

Newer engines have made great strides in improving efficiency, and the GX has a 6-speed transmission instead of a 4-speed, which counteract the larger drag of the boxier shape.

The weight doesn't matter that much on the highway.

Does the GX460 have an overdrive gear for highway cruising?