We demonstrate a novel way of creating three-dimensional microfluidic channels capable of following complex topographies. To this end, substrates with open channels and different geometries were 3D-printed, and the open channels were consecutively closed with a thermoplastic using a low-resolution vacuum-forming approach. This process allows the sealing of channels that are located on the surface of complex multiplanar topographies, as the thermoplastic aligns with the surface-shape (the macrostructure) of the substrate, while the microchannels remain mostly free of thermoplastic as their small channel size resists thermoplastic inflow. This new process was analyzed for its capability to consistently close different substrate geometries, which showed reliable sealing of angles >90°. Furthermore, the thermoplastic intrusion into channels of different widths was quantified, showing a linear effect of channel width and percentage of thermoplastic intrusion; ranging from 43.76% for large channels with 2 mm width to only 5.33% for channels with 500 µm channel width. The challenging sealing of substrate ‘valleys’, which are created when two large protrusions are adjacent to each other, was investigated and the correlation between protrusion distance and height is shown. Lastly, we present three application examples: a serpentine mixer with channels spun around a cuboid, increasing the usable surface area; a cuvette-inspired flow cell for a 2-MXP biosensor based on molecular imprinted polymers, fitting inside a standard UV/Vis-Spectrophotometer; and an adapter system that can be manufactured by one-sided injection molding and is self-sealed before usage. These examples demonstrate how this novel technology can be used to easily adapt microfluidic circuits for application in biosensor platforms.