Descend and ascend of deep-water human-occupied submersibles based on buoyancy changes are enabled using a denomination of dispensable drop-weights, and loss of buoyancy are managed using emergency drop-weights and jettisoning identified systems. Failing to release the drop weights or jettison results in submersible stranding on the sea floor, leads to emergency recovery, and hence the drop-weight configuration has to be highly reliable. The paper, for the first time, based on hydrostatic stability, descend/ascend velocity needs, ocean salinity profile and loss-of-buoyancy situations, proposes a novel on-demand reliability based methodology for determining the safe drop-weight configuration and degradation-based mission abort strategy for deep-ocean human submersibles. Probabilistic on-demand reliability analysis based on IEC61508 standards for safety–critical systems using component field-failure data is carried out and the drop-weight configuration essential to meet the human-rated safety integrity level 3 during all stages of the subsea mission is identified for the deep-ocean human scientific submersible Matsya6000, based on which a mission abort protocol is evolved.