The Borderlands franchise has a long and somewhat complication storyline that has progressed through all the series titles. As with any story of this length and magnitude, many moving parts can sometimes get lost in the mix of things. Unfortunately, sometimes these can create holes in the story, that doesn't make sense in the current story without further explanation. As the fifth title in the series, Borderlands 3 pays off some of the storylines that started earlier in the franchise. It also creates some inconsistencies within the story that leaves us scratching our heads.
10 The Watcher
At the very end of Borderlands: The Pre-Sequel Lilith moves to execute Athena after she tells the story of how she helped Handsome Jack come to power on the moon. Right before Athena is sent to the afterlife the mysterious Watcher comes in and saves her. He tells Lilith that there is an imminent war coming and they would need all the vault hunters they can recruit. Apparently, this isn't that fight because it only takes a couple of vault hunters to dispose of this threat. Based on this it's safe to assume the Watcher overestimated the Calypso twins or has a different understanding of the word "imminent."
9 Calypso Twins Rise To Power
Borderlands 3 needed a villain and there weren't any existing characters ready to fill that void, so new characters needed to be introduced. That said, the lack of explanation for how the Calypso twins rose to power and what Lilith and the crimson raiders were doing during that time is frustrating. With the Commander Lilith & the Fight for Sanctuary DLC, we know the crimson raiders lost their home but Borderlands 3 takes place years after the fact and they have done nothing but hang out twiddling their thumbs.
8 Dr. Zed
This isn't that much as a plot hole as the rest of these because it could very easily be explained but where is Dr. Zed? He is just not around, at all. This is super weird since Marcus and Moxxi both got rounded up and put on Sanctuary 3. Crazy Earl even got onto the ship, so it doesn't stand to reason that they couldn't get Zed on. Every health vending machine in the game, even on the different planets, is Dr. Zed branded so he has certainly been busy lately. There is even a medical area where he could go, that instead holds Tannis, who has never been shown to be a medical doctor.
7 Other Vault Hunters
After Borderlands 2 is expected that the playable vault hunters from the previous game will show up at some point. Borderlands 3 does exactly hit the mark on this with only Zero and Maya showing up as the safety of the entire universe is at stake, and they show up in odd ways. Axton, Salvador, Gaige, Krieg and Athena don't make an appearance in the game at all. Considering the first four helped out Lilith as recently as her DLC, it's safe to say they are all on good terms.
6 The Eye Of The Destroyer
Borderlands 3 reveals that the Destroyer was not killed but simply pushed back in the original game which almost seems plausible. However, in Borderlands: The Pre-Sequel Handsome Jack reveals that he acquired the eye of the destroyer and used it to create the Helios Moonbase laser. If the Destroyer wasn't killed and just shoved back into the portal this doesn't work, unless you believe it's eyeball fell out. It certainly throws some curveballs into the story that don't hold much water.
5 Rhys and Fiona
Tales From The Borderlands ends with Rhys and Fiona being teleported off after opening the vault. While the "canon" outcome isn't known, Rhys and Fiona can have a very strong relationship at the end of the game so to have Rhys appear as the CEO of Dahl with no mention of Fiona is certainly odd. While it is entirely possible that they just when their separate ways afterward, there would most likely need to be some type of event to cause a rift.
4 Siren Power Transfer
The concept of siren's powers transferring when they die is introduced in this game with a pile of questions they don't answer. It's hard to say if this was planned for in the previous titles but it seems like it would have been mention prior. The echo recordings of the sirens in the game so far indicate that the majority of them had powers manifested at birth or shortly after. It also seems that the powers get transferred to somebody the siren knows, or it does in the case of Tannis and Ava, which raises even more questions about the nature of the siren powers.
3 Brick, Mordecai and Tina
This trio is handled oddly in Borderlands 3. They appear as a spec ops team on Eden-6 working for Wainwright Jakobs attempting to rescue Hammerlock from prison. After that mission, they aren't seen again until a couple of side quests back on Pandora. Tina talks on the Echo during the raid on the twin's cathedral and gives one of her pizza bombs to Ava to open a door but that's it. They don't come to Sanctuary and aren't involved in the plot besides that. It feels dismissive of their character growth from the second game.
Based on Rhys being the CEO of Dahl, it means that the canon choice from Tales From The Borderlands means that Hyperion is pretty much out of business at the end of that game. It begs the question of how they are still operating in Borderlands 3 and how much of a comeback the company has made. With New-U stations all over the place and new weapons being manufactured it looks like they are operating (slightly less evil) business as usual. Who is in charge and where are they operating out of?
1 Crimson Raiders
The title of Crimson Raiders must just be Lilith trying to hold on to some semblance of order because there aren't any members of the raiders around. Lilith might be counting the town folk both on Sanctuary 3 and in Roland's Rest but there aren't any raiders around. Some friendly NPCs show up during a story mission or two but are gone most of the time. The actual red soldiers seen in Borderlands 2 must have decided to leave once Handsome Jack died because they are nowhere to be found.