When looking at Supergirl to compare the big bads, it's a little tricky. You aren't quite sure who the big bads are — they don't quite conform to the same format as the other series. And there are still three episodes left, so there's nothing to say that things might not drastically change. But will take a look at them for now and update later if needed. This season has been all about Reign. I would've said all about the Worldkillers, but the other two weren't around very long, were they?
The first season followed the format of the other Arrowverse series and put Supergirl up against someone with similar abilities and that she used to trust. In this case it was her Aunt Astra (Laura Benanti), who led a group of Kryptonians, along with Non (Chris Vance), in an effort to take over the Earth and make it into the a new version of Krypton. But there was also a sub-villain, Maxwell Lord (Peter Facinelli), who was the human villain as opposed to the alien villain. Astra made for an interesting and sympathetic villain at the end of the day, but she wasn't that memorable either.
Season 2 moved to The CW and the show changed a few things, jettisoning Lord but keeping the Human villain and Alien villain dynamic. In this case the human villain was Lillian Luthor (Brenda Strong) and we had two sets of alien threats, starting out with White Martians and then turning to Daxamites led by Rhea (Teri Hatcher). The show likes having the human villain having to help out against the alien villain, but in this case it was Lena Luthor (Katie McGrath) that really helped and took the Maxwell Lord place on the series.
With the third season they introduced the threat of Reign early on, showing us Samantha Arias (Odette Annable) as a human first and letting us like her before she became the Worldkiller. They also introduced a Selena (Anjali Jay) as a guide for the Worldkillers and Thomas Coville (Chad Lowe) a human cult leader. Reign is similar in abilities to Supergirl but more powerful, especially after the death of the other two Worldkillers, but her Sam side is a weakness. And it looks like we may end up with Selena being a master manipulator and having pulled all the strings.
Ranking these is interesting with the fact we have three episodes to go and maybe the big bad isn't really the big bad. But I'm going to assume that Reign is the one we are considering. In which case I think Reign has the best story line so far and has been the most sympathetic as villains goes. When it comes to the second and third place, that's where it gets tricky because of the split villain setup and the fact that Astra just wasn't that strong a villain. Rhea is, but she was only around for part of the season. So I have to look at the combined set of villains for the season, and I think Rhea/Lillian/White Martians take the second slot over Astra/Non/Maxwell Lord.
I hope that next season they go with something completely different, perhaps a magical villain.