Is there any way to buy the Humble Bundle with a PaySafe card or Skrill in 2021?

I don't think so friend. Try PayPal. It is awesome.

If they are connected to visa or mastercard, yes. Just put your card number just like paying it with a credit card.
If not, then i doubt it.

Short answer no. But you can convert paysafe card pins into paypal or a prepaid credit card using this site https://ukash-wallet.com/index.php?do=paysafecard-trade