The ISA leaves something to be desired for "simplest". Simple, sure, but parameters (and unused ones, at that!)? Memory copy instructions? Multiply and no shifts? Addition _and_ subtraction?
Others have mentioned Subleq (Subtract And Branch If Less Than Or Equal To), but there's more useful designs that meet all the design constraints. They state that "It is also not intended to be as simple and elegant as it could possibly be.", but it's called "The Simplest Virtual Computer" - that kind of name is a challenge.
For what? The simplest possible ISA? Something like an OISC or a ZISC, probably. Simplest "virtual computer"? Maybe the SK(I) combinator system? Specific improvements to this architecture? My personal preference would be to ditch the three arguments that aren't always used, have two 8bit instructions per 16bit word, use a stack (to eliminate the operands). But that's just one mode of thought for a very simple computer, not the only one. This line of thought is particularly inspired by the F18 Forth chips. They're quite minimal, simple, tight CPU designs: https://www.greenarraychips.com/home/documents/greg/DB001-22...
Others have mentioned Subleq (Subtract And Branch If Less Than Or Equal To), but there's more useful designs that meet all the design constraints. They state that "It is also not intended to be as simple and elegant as it could possibly be.", but it's called "The Simplest Virtual Computer" - that kind of name is a challenge.