Almost all of mine have been said so most of these will be me seconding:
I read mental-floss which led me to their YouTube Videos which led me to John Green which led me to Crash Course which led me to Vlogbrothers and those are all channels I now watch and enjoy.
Cinema Sins and Honest Trailers.
CGP Grey and The Idea Channel
Belated Media is good but he rarely posts stuff.
I play Magic The Gathering so I watch The Magic Show
And one that ended up underwhelming: I had high hopes for Geek & Sundry but find that other than Tabletop I don’t watch much on it.
If we’re going to include web series you don’t watch on YouTube I would also include After Hours. And Redlettermedia’s Half in the Bag (both of which I guess are on YouTube but I don’t watch them there).
I second The Brain Scoop. Emily is adorable, and the videos are both fun and informative, but here’s a warning; if you are the least bit squeamish, DO NOT WATCH the video called “Squirrel McNastyface”.
No love for Stuart Ashens so far I see (Ashen still has his “best of” video on his main page, which unfortunately autoplays loudly starting with the Troll doll Hitler joke - so beware).
Along those lines, Larry Bundy Jr. (Guru Larry) often does some rather funny video game reviews, sometimes in conjunction with Ashens and others…
Anyway, I’m fond of watching John Green play FIFA 2014 on the HankGames channel; he’s made up songs for some of his players, not to mention backstories and so on. Also, he gives all of the income from the channel to the actual AFC Wimbledon club, a second or third-tier English football club that’s owned by its fans.
The JBL & Cole Show is one of the best things the WWE puts out each week. Hilarious and often a touch surreal.
YouTube Comment Reconstructions, in which two older English actors who absolutely dripped gravitas with every word acted out YouTube comment conversations, was brilliant, but it seems to be done now, sadly.
SFDebris and a lot of the channels made by Brady Haran. I also like watching Ellen. I’m also partial to PushingUpRoses, but I doubt any of you would be into her.