Introduction Sodium reduction in the human diet is currently one of the main concerns for public health agencies and, consequently, has become a challenge for the food industries. The World Health Organization has proposed to reduce sodium intake by 30% in order to obtain the WHO guideline of 2 g/day (i.e., 5 g of salt/day) by 2020. Cheese is perceived as being a food source that is highly concentrated in sodium, with amounts that can vary depending on the type of cheese. The objective of our study was to investigate the effect of reduced salt content and partial substitution of NaCl with KCl on the quality of soft and semi-hard cheeses using a combination of multi-omics, biochemical and sensory approaches. Materials and Methods Soft (camembert-type) and semi-hard (reblochon-type) cheeses were prepared from pasteurized milk and inoculated with specific starters and spoilage microorganisms when appropriate. Different salt contents were taken into account: standard level, 1.5 g/100 g of cheese; reduced level, 80% of NaCl level; and substitution level, 80% of NaCl and 20% of KCl levels. The cheeses were incubated in a ripening chamber for 21 days at 11°C or 13°C. They were sampled at days 1, 7, 14 and 21. The analyses included physicochemical and biochemical composition, microbial counts, 16S rRNA gene metabarcoding and metatranscriptomic analysis, volatile aroma compounds and sensory analysis. Discussion Regarding soft cheeses, the salt content of cheeses affected proteolysis at 21 days of ripening. The relative activity of G. candidum increased, whereas that of P. camemberti decreased in reduced salt cheeses in comparison to the controls. Higher global intensity of odor and taste was observed in cheeses with reduced salt content, consistent with higher levels of alcohol and ester components. Regarding semi-hard cheeses, modifications of salt content did not significantly affect either their biochemical parameters and sensory characteristics or their technological microbial composition at day 21 of ripening. Finally, no impact of salt content was observed on the growth of the spoiler Yarrowia lipolytica in soft cheeses. In contrast, reducing salt content increased spoiler growth in semi-hard cheeses, as highlighted by a greater development of Pseudomonas that led to an increase in cheese proteolysis and lipolysis. In conclusion, the effect of reducing salt content is highly dependent on the cheese type. This factor should thus be taken into account by the dairy industry when the reduction of salt content is being considered. Moreover, the quality of raw products, in particular, the level of spoiler microorganisms, must be controlled before use during dairy processes.