As a rule of thumb—or as the British say, a rule of big toe—if some object is in the title, we should ask what the big significance of that thing is. We're not talking about the title of Adams's book here; we're talking about the Hitchhiker's Guide to the Galaxy within The Hitchhiker's Guide to the Galaxy—you know, the book Arthur keeps consulting to help him figure what on earth—if earth still existed—is going on. Where does the Hitchhiker's Guide show up in the book and what meaning might it have? The Guide is kind of a big deal here, so let's take it apart piece by piece (and try to remember how to put it together again).
Word Limits… or World Limits (How the Guide emphasizes Setting)
First, let's talk about the object itself. The Guide is an electronic book, so it has a huge amount of memory, but it's not unlimited. Even if this electronic book has a giant amount of memory, a giant memory is no match for the giant, giant, giant universe (see "Setting"). So the fact that this book only describes Earth as "Harmless" (original) or "Mostly harmless" (expanded entry) helps drive home the idea that Earth is not all that important to most of the species in the galaxy.
We should mention that in the late 1970s, when Adams was writing the radio show that would become the book, the idea of an electronic book would seem a lot more science fictional than it does in the 21st century. Adams also wouldn't have had iPads and Kindles to look at, so that's one reason why the Guide resembles "a largish electronic calculator" (3.3) rather than a suave, shiny tablet.
Digressive and Guide-y
The Guide functions in the same way for the characters in the book as it does for us. Like Ford Prefect (and later Slartibartfast), the Guide is a useful and convenient way to get info, such as the story of the Babel fish (Chapter 6) to Arthur and to readers. The Guide also provides material for the narrator's digressions and funny stories, like the story of Veet Voojagig, the guy who thinks that ballpoints are alive and have a planet of their own (Chapter 21). Now, if you think "tells us useful information" doesn't fit with "goes off on random digressions," you might be right—and that tells us something about the meaning of the book, which is…
So what does the Guide symbolize? What's so important about it? Yeah, it's got a chill title, and yeah, Ford is supposed to be a searcher for it, but let's be real: you could rewrite this book and leave the Guide out completely if you wanted to. Just think what would happen if Ford were an alien who came to visit and explain everything. It would totally work. So what's so meaningful about this book? Why put it in at all?
One thing that makes the Guide notable is that it's not always correct, and we're of the opinion that that's kind of a problem for a reference work. This is a book that's really more about truthiness than about truth. The narrator comes out and tells us, "The Hitchhiker's Guide to the Galaxy is a very unevenly edited book and contains many passages that simply seemed to its editors like a good idea at the time" (21.3). Now, that makes the Guide sound a lot like Wikipedia, with giant entries on Marvel Comics and tiny entries on real wars in Africa.
In fact, sometimes this Guide is less a guide and more like a snarky but misinformed friend. For instance, instead of giving information about what alcohol is in a scientific sense, the Guide gives a recipe for a very powerful drink (2.2.). And when the issue is the marketing division of the Sirius Cybernetics Corporation, the Guide is rather free in its opinion that they are "a bunch of mindless jerks who'll be the first against the wall when the revolution comes" (11.57). That wouldn't even fly on Wikipedia.
This all makes it seem like it's really hard for people (er, aliens) to come up with accurate and useful information about the galaxy. There may be useful information in the Guide, but it's just as likely to give you a digression on Antarean parakeet glands when you don't need it, (Do you ever need it?) If the Guide has become "the standard repository of all knowledge and wisdom" (Introduction.14), then it sounds like we don't have enough knowledge and wisdom. And we could certainly see the Guide as symbolic of our defeat: the universe will always be bigger and more complex than we can understand. This is especially true when our commitment to the truth is mixed up with our desire to save some money and drink alcohol.