- Breaking up with a sweetheart or spouse
- Having their apology being rejected by a friend after a fight.
- Being rejected by their crush after a confession, having their crush choose a love rival, or possibly having another Mii steal their sweetheart.
- Being told not to confess their feelings
At the Mii's apartment there will be morose music to fit the situation and they Mii will say that they're feeling down. When they are sad a rain cloud or some purple embers (JP) can be seen floating above their head (Around their head in the case of the latter). Additionally, there will be a thought bubble with a face of the Mii who they fought with, broke up with, or had rejected them.
The sad Mii's happiness meter will also deplete entirely and will be replaced with sadness points.
There are multiple ways to deplete sadness or cure it instantly:
- Feed them food or give them new clothes, with the caption being "[He/She] likes it!" or better.
- Give them a new interior that is at least their favorite.
- Give them a travel ticket. (Instant cure)
- Feed them their all-time favorite food/super-all time favorite food. (Instant cure)
- Have another Mii find the sad Mii a sweetheart. A successful setup will diminish all sadness.
- If the sad Mii was rejected by a love interest, occasionally they might want to try to confess to the Mii once again, and if the Mii gets accepted their sadness will be instantly cured.
- If the Mii is rejected again, the Mii will sometimes say that they are "ready to let go", instantly curing all sadness.
- If the Mii's apology was rejected, and the friend's name is still on the Mii's relationship chart under "Friend (Fight)", as long as the Mii who rejected that Mii's apology still has an orange problem icon, the asking Mii will say that they're sick of fighting and want to apologize. It is an instant cure once the apology is accepted.
- Have another Mii become friends with the sad Mii and if it all goes well, the Mii's sadness will be removed.
- Have a Mii that has feelings for the sad Mii confess. It's an instant cure if the confession gets accepted.
- Delete the Mii who rejected the sad Mii. No reward will be given.
- Completely ignore the Mii for 2-3 days (or rarely only 1 day).
- When a sad Mii's apology is rejected by a friend or has broken up with someone, they both have flashbacks when the player clicks their thought bubble. The rejected Mii's flashback show them and the Mii who rejected their apology after fighting. The ex's Mii's flashback shows them and their ex-sweetheart having happy times. There is also another version for the flashback for breakup when a Mii's ex-sweetheart ditched them for someone else. This will not happen with spouses, however.
- If a couple breaks up, there's a chance only one Mii will gain sadness if the other Mii ditched their ex for someone else, though rare.
- It should be noted that "depression" is an inaccurate term for this condition. Depression is more than the ordinary type of sadness most people feel. 
- There's a chance that you can see an Easygoing Mii crying from their apartment view.