nathan fillion seems to get mentioned bunches because mal reynolds is big homage to han solo.
but i honestly think another joss alumnus, alexis denisof (wesley wyndham-pryce), would be more interesting in the role. he developed a lot of range, and played both the book nerd and the super badass (alexis isn't actually british in real life).
nathan fillion never was on any of the shows long enough to really show half as much range. i'd mention david boreanaz as somebody who seems like he should be a manly, but vulnerable hero in bigger roles... but he's built too much like a football player, whereas alexis is more of the early 20th century tall but slender body build--and looks great with stubble. indy strikes me as being on the lean side and alexis is more that than both nathan and david. alexis also has an extraordinary emotional range--from goofy dork comedy to depression, sadism and pathos. he's great at being a brainy anti-hero.
anyway... i can see alexis as an action hero and part-time professor more than nathan fillion, who doesn't strike me as being someone who could pass for a professor-type. though, fillion has the deeper/stronger voice.
seriously though, joss whedon's cast members are seriously underrated and it seems like hollywood doesn't find them mainstream enough, despite the massive buffy/angel/firefly fanbases--the diehards rival the star wars and indiana jones fanbase. angel is the best of whedon's shows, btw. the first 3 seasons of buffy are classic, though. firefly was disappointing to me (it really hadn't taken off when it was canceled--the movie was closer to what i'd expect from the end of a joss season than even a full story), but i liked serenity, as it felt a lot more like btvs/ats (especially the focus on river, who is a bit of a take on drusilla--joss has a thing for mental triggers and psychotically damaged individuals with special gifts).
the main hollywood casting machine totally looks past them despite so many fans wanting them to do real stuff. david and alexis, imo, are the two i think should be given some big chances and would do well in a variety of roles.
but of course, at the end of the day, there is only one indiana jones: harrison ford.