Prevention of delamination failures by improved design calls for accurate characterization and prediction of mixed-mode interface delamination. In this paper, a combined in situ experimental-numerical approach is presented to fully characterize the interface behavior for delamination prediction. The approach is demonstrated on two types of industrially-relevant interface samples – coated copper lead frame-black molding compound epoxy and uncoated copper lead frame-white molding compound epoxy, – for which the delamination behavior is characterized in detail using a miniaturized in situ SEM mixed-mode bending setup and simulated using a newly developed self-adaptive cohesive zone (CZ) finite element framework. To this end, mixed-mode load-displacement responses, fracture toughness versus mode angle trends, and real-time microscopic observations of the delamination front are analyzed to determine all CZ parameters. The various simulation results are found to be in agreement with experiments for the range of mode mixities accessible, demonstrating the ability of the characterization procedure to accurately obtain the cohesive properties of different interfaces, as well as the stability and efficiency of the self-adaptive CZ framework.