Reservoir simulation workflows contain significant elements of uncertainty, particularly in the geological description of reservoir geometry and petrophysical parameters such as permeability and porosity. To accurately account for uncertainty and span the range of likely outcomes, different equiprobable realizations should be kept as long as possible throughout a modelling workflow. However, working with multiple realizations of the same reservoir for optimization purposes may quickly become prohibitively expensive, particularly since using a full forward simulation can be quite demanding even for a single model realization. Herein, we propose to combine two recent and quite different technologies to enable optimization of multiple realizations. The first is the use of multiscale technology, wherein approximate, but well-behaved pressure solutions can be efficiently computed using precomputed basis functions that capture local flow features. Secondly, the use of single-phase flow diagnostics can serve as an efficient alternative to full physics flow simulations for optimization and characterization purposes. By combining these technologies in a single implementation, we obtain a workflow that makes it possible to quickly evaluate and optimize multiple realizations, while still retaining error control. In particular, it is possible to adjust accuracy dynamically from inexpensive proxy models provided by pure multiscale and flow diagnostics, via more accurate iterated multiscale solutions and incompressible flow, to fully-implicit solvers that incorporate the relevant flow physics.