We describe an optimized digital holographic microscopy system (DHM) suitable for high-resolution visualization of living cells under conditions of altered macroscopic mechanical forces such as those that arise from changes in gravitational force. Experiments were performed on both a ground-based microgravity simulation platform known as the random positioning machine (RPM) as well as during a parabolic flight campaign (PFC). Under these conditions the DHM system proved to be robust and reliable. In addition, the stability of the system during disturbances in gravitational force was further enhanced by implementing post-processing algorithms that best exploit the intrinsic advantages of DHM for hologram autofocusing and subsequent image registration. Preliminary results obtained in the form of series of phase images point towards sensible changes of cytoarchitecture under states of altered gravity.