Safest winter route from San Diego to Des Moines

I'd just check weather on the day of departure and then decide. The southern route is probably a little less likely to have snowy or icy conditions on any given day in winter but either route can be bad when the other one is not.

As noted above, the weather will be worst on February 20th where it's the worst on February 20th -- and that's something you only know with absolute certainty till that date.

I'd make initial plans for I-8 from San Diego to Casa Grande, I-10 to Las Cruces, I-25 north to Albuquerque [don't make a wrong turn there! :^) ], I-40 east to Oklahoma City, and then I-35 into Des Moines. This route is LESS likely to have bad weather, but check the Weather Channel on the 20th to be certain.

The advantage of going interstates the entire way is that these will get priority for being kept clear. The disadvantage was summed up by Charles Kuralt -- you won't see anything.

Do either of you have experience driving in snow? Not many cars in San Diego have snow tires. Are either of you coming back to sunny California?
It is a solid 12 hour drive to Albuquerque in good weather.
Please check your tires (pressure/tread). If it starts to snow pull off the interstate at the first exit that has lodging and wait until it stops snowing.

I'm assuming you've done a search on Mapquest or Google maps of the various routes.

The shortest route I'm seeing is through Las Vegas/Grand Junction and Denver. There's really only a short stretch of that route that is in the mountains, the stretch between Grand Junction and Denver. That section is all interstate and you'd be in the mountains for less than 4 hours.

I don't know that I would re-route and add several hundred miles to the trip just to avoid a 3 hour stretch of interstate, especially with the ability to check the weather forecast ahead of time. There are certainly potential pitfalls anywhere on that route - ice storms are more likely on the southern route than snow, and I'd much rather drive on snow than ice.

Storms can be massive or very localized so as everyone else says, you just need to check the weather and adjust accordingly. The roads in Colorado could be perfect while New Mexico could be hit with a huge storm.

Both routes have the potential for terrible driving conditions. We have often driven between Denver and Des Moines and hit terrible ice storms in Nebraska. We spent hours sitting in our car on the road, along with everyone else, because Rt. 80 was a solid sheet of ice.

The route through Oklahoma, Kansas and Missouri into Iowa can also be very bad in winter.

I advise you to check the conditions the day before you plan to leave, and plan your route accordingly. Be sure to have emergency stuff with you: warm clothes, flashlights with extra batteries, charged cell phones, water and food. And be sure someone knows what route you plan to take.