We propose a method for the spectral analysis of unbounded operator matrices in a general setting which fully abstains from standard perturbative arguments. Rather than requiring the matrix to act in a Hilbert space H, we extend its action to a suitable distributional triple D⊂H⊂D− and restrict it to its maximal domain in H. The crucial point in our approach is the choice of the spaces D and D− which are essentially determined by the Schur complement of the matrix. We show spectral equivalence between the resulting operator matrix in H and its Schur complement, which allows to pass from a suitable representation of the Schur complement (e.g. by generalised form methods) to a representation of the operator matrix. We thereby generalise classical spectral equivalence results imposing standard dominance patterns.The abstract results are applied to damped wave equations with possibly unbounded and/or singular damping, to Dirac operators with Coulomb-type potentials, as well as to generic second order matrix differential operators. By means of our methods, previous regularity assumptions can be weakened substantially.