Back when Lovecraft was writing his stories, there wasn't the neat distinction between horror, fantasy, and science fiction that currently exists. It was all kind of shoved together under the label of Weird Fiction, so you get stories like John Carter of Mars psychically transporting himself to Mars, or magic-wielding aliens, or--more topically--Lovecraft's At the Mountains of Madness, which has this quote when referring to the Old Ones:
"Radiates, vegetables, monstrosities, star-spawn - whatever they had been, they were men!"
That's the approach that Eldritch Skies takes, and right from looking at the human/mi-go trade mission on the front cover, you know that this isn't going to be like Call Of Cthulhu, or as I often call it, "The Dunwich Horror: the RPG." Aliens are alien, but they're not innately inimical to humanity, and while you'll never have a human and a mi-go drinking together in a bar after work and complaining about their bosses, it is possible for them to interact and get beneficial results for both parties.
Eldritch Skies actually reminds me a lot of Eclipse Phase. Not because of the specific details--the kind of society Eclipse Phase demonstrates is probably intrinsically destructive and dehumanizing in the world of Eldritch Skies--but because of the overall structure. The PCs are assumed to be part of an organization that's tasked with solving various problems that pop up as humanity expands out into the cosmos, the threat of total extinction is hanging over humanity's head, a lot of offworld colonies are based on exploring alien ruins, and so on. This is a good thing, because Eclipse Phase is excellent.
Anyway, what makes Eldritch Skies a sci-fi Lovecraft take other than that the players can talk to the horrible monsters as well as be eaten by them? Part of it is the approach to world-building it takes. When discussing the structure of the universe, the book (albeit obliquely) refers to the Great Filter in the discussion of the fate of every space-faring species. The vast majority of species either go extinct or transcend, though some species find a stable equilibrium and stagnate as their psychology prevents them from making any new technological discoveries unless they experiment with alien technology, and some species try to transcend and screw up or only partially transcend, leading to creatures like the flying polyps or the star-spawn of Cthulhu.
Hyperspace mentioned above is how a lot of the Lovecraftian metaphysics and background is all tied together. Humans who gain "hyperspace exposure" can become psychic, and psychic powers or sorcery can cause hyperspacial exposure, as can alien artifacts based on hyperspacial principles, or even simply traveling through hyperspace (which makes the colonies perhaps more dangerous than they otherwise might be...). Humans exposed too much develop an increasingly inhuman mindset, and eventually transform into hideous monsters. This is the source of ghouls and deep ones.
Similarly, hyperspace is where the servitors of the Outer Gods and the Great Old Ones live. In Eldritch Skies, Great Old Ones might be natural, or they might be the result of certain individuals transcending, or possibly the amalgamation of an entire species transcending. Servitors and Great Old Ones typically don't have much contact with the physical world unless they are summoned or something catches their interest, and one of the ways to attract their notice is...high levels of hyperspacial exposure. This is one of the reasons why extinction is so common: a species begins experimenting with hyperspace, an experiment goes hideously wrong, Cthulhu or the alien equivalent takes notice, and millennia later some other species exploring its local surroundings finds a world with its atmosphere blasted away, or evenly-spaced craters covering the entire planet's surface, or perfectly preserved ruins with no trace that anyone ever lived there, and so on.
This is another point I think connects it to Eclipse Phase--humanity's exploration of the cosmos is probably the only thing that will ensure its survival as a species, but at the same time, it makes it far more likely that humanity will attract unwanted attention leading to its total extinction.
There are a few planets listed here that humanity has discovered, including Firefly, where almost all life is part of vast communal organisms called "metas"; or Colossus, which experiments indicate is actually a Dyson sphere built around a gas giant and has a surface area 300x that of Earth; or Eridanos, where some old catastrophe boiled off the oceans and rent the planet with giant rifts into which life had to descend to survive; or Galatea, where humans used sorcery to travel there millennia ago and the planet is a series of city-states ruled by sorcerer-kings like something out of The Coming of Conan the Cimmerian. If some of these sound similar to some of the planets in Gatecrashing, that's because they are, but the similarity is pretty superficial, and anyway Galatea is way more similar to Stargate. And frankly, that's fine to me, because Lovecraftian Stargate is great tastes that taste great together.
I haven't been talking about the mechanics at all, but that's mainly because I don't really like Unisystem. It's a perfectly fine system, it's just not for me, so reading the system parts of the book mostly either put me to sleep or made my eyes glaze over. I bought Eldritch Skies for the fluff anyway so I don't mind, but you might have another opinion.
This gets four stars only because there are huge portions of the book I can't use and that actively resisted my reading them. Taken solely on the fluff and ability of the book to inspire, it's five stars all the way. If you're tired of reading interpretations of Lovecraft that read more like Gnosticism, where the universe is intrinsically inimical to humanity specifically and every non-human species has it out for humanity and the only possible fate is madness and death, Eldritch Skies is an excellent antidode.