I had no trouble running season 21 on my 2018 Mac mini i7, Catalina and RX580 eGPU. Unfortunately, Diablo III loads only to a black screen with an oversized arrow cursor and audio with the same hardware and Big Sur. If I disable ‘Prefer External GPU’, Diablo will load to the menu screen but with the expected performance hit. I have deleted and reinstalled Diablo III with no resolution.
2020-12-07
Issue still present on version 2.6.10.71814.
2020-12-14
Well, it worked for a moment… I installed a new monitor tonight (upgrading from ultra-widescreen to 2k). When I launched D3, it opened in a window and displayed properly with the eGPU enabled. When I changed the display to Fullscreen and relaunched, I was back to the black screen with oversized arrow icon. Obviously the issue is resolution-related, but I just cannot find the right combination to get it to work…
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Exact same issue here- D3 working fine before I installed Big Sur.
RX580, eGPU. I get a blank screen with the cursor on it, the game sounds are happening OK but nothing else on-screen 
Have tried setting the game to launch in Windowed mode but the screen is still blank if the eGPU is set to be preferred.
Update- I connected a dummy HDMI connector to the RX580, set the displays to mirror and it started working.
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Aaand much like OP’s experience, after I disconnected and reconnected the eGPU it no longer worked.
Had to reset the mirroring/scaling options to get it to work again.
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I’m having this same problem with multiple games (and have been for a while). Very frustrating, since the egpu was working fine for a full year… and then I updated to Big Sur. Did anybody find a solution that works for them?
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Hi all, it’s 2023 and monterey 12.6.5 system, the problem with the black screen on egpu remains, it looks like blizard scored on it all. And the solution to the problem can not wait, unfortunately.