Not sure this is a valid dichotomy.
If you are spinning up multiple clusters, you are presumably doing so in an automated fashion. If so, then the effort of hardening is very similar. It doesn't really matter where you do it.
Multiple clusters may have a smaller blast radius, but will have a larger attack surface. Things may be shared between them (accounts? network tunnels? credentials to a shared service?) in which case an intrusion in one puts everyone else at risk.