We determine simplicity criteria in characteristics 0 and $p$ for a ubiquitous class of iterated skew polynomial rings in two indeterminates over a base ring. One obstruction to simplicity is the possible existence of a canonical normal element $z$. In the case where this element exists we give simplicity criteria for the rings obtained by inverting $z$ and the rings obtained by factoring out the ideal generated by $z$. The results are illustrated by numerous examples including higher quantized Weyl algebras and generalizations of some low-dimensional symplectic reflection algebras.