A flip-chip sample imaging device with self-aligning lid includes an image sensor chip, a fan-out substrate, and a lid. The image sensor chip includes (a) a pixel array sensitive to light incident on a first side of the image sensor chip and (b) first electrical contacts disposed on the first side and electrically connected to the pixel array. The fan-out substrate is disposed on the first side, is electrically connected to the first electrical contacts, forms an aperture over the pixel array to partly define a sample chamber over the pixel array, and forms a first surface facing away from the first side. The lid is disposed on the first surface of the fan-out substrate, facing away from the first side, to further define the chamber. The lid includes an inner portion protruding into the aperture to align the lid relative to the fan-out substrate.