Can I use I18N or another module to house regional variations of a site in a single installation? I have a large build coming up and am planning to attack it in Drupal 8.

The client will have three regional variations of their site, a .com, a .co.uk, and a .es. The goal is for them to look like one site. The sitemap will be 98% symmetrical between the three sites, only a handful of pages may exist in one menu and not in another. The .es will be in spanish, the .co.uk will be in UK English, .com in US English.

Is there any better way to approach the three sites that would make it easier to manage? For instance, using I18N? Having translations of each region is not a requirement, and almost every page will be shared between all three, with language variations (in .co.uk probably changes for SEO sake so we don't look like duplicate content).

Thank you for any input!
Af far as building and configuring such a project relying on Drupal multilingual features is a no-brainer, you should definitely go that way. Entering content in different languages has to be done either way, but with the multilingual setup, you don't have to repeat the work you do around the structure. 

There probably is a very small number of special cases where not using multi-lingual features would be faster. Cases where you build one site, polish it, then just clone and do tiny adjustments for the other two languages. But the reality of web projects doesn't make it very probable that your project specs and necessary ongoing work will be so clearly defined to justify avoiding the multilingual setup. 

Detection and Selection of Languages will allow you to choose URL as the detection method, and further in that configuration, you choose Domain (instead of the Path prefix) as the Part of the URL that determines language. 

You'll have to do some planning around the menus, which ones you can share and translate, and whether you'll need to create some language-specific menus. 

You'll be able to have language-specific paths, dates, other configuration... I found multilingual projects always take a lot more time to build than it seems, so don't underestimate it. It's not simply entering all the translated expressions into some interface and you're done. You have to learn about different places where to setup the structure for different languages etc. But in the end, it is faster to setup and maintain one site with multilingual features and translate it, than it is to build and maintain 3 separate ones. 

Definitely learn about Hreflang for multilingual SEO, there's a link to Google support page explaining it there.