The NLRP3 inflammasome is a key intracellular component of the innate immune response. It is a three‐protein complex essential for the production of mature interleukin 1‐β. The complex, which is comprised of three proteins, NLRP3, ASC, and pro‐caspase‐1, has been implicated in the physiological response to pathogenic elements of cardiovascular disease and Alzheimer's disease. Investigations into the properties of the three proteins can be aided by larger‐scale recombinant expression to produce adequate amounts. In the current study, a variety of NLRP3 inflammasome proteins were expressed in the ExpiCHO‐S mammalian cell system with a particular focus on ASC. ASC fusion proteins with glutathione‐S transferase, maltose‐binding protein, and SUMO increased solubility and aided in determining the stability and oligomerization propensity of individual ASC domains and full‐length ASC. ASC oligomerization was highly sensitive to protein concentration, ionic strength, and mutation. These observations provided strategic ways to enhance protein purification and characterize ASC oligomerization. The ExpiCHO‐S expression system consistently produced high‐yield recombinant NLRP3 inflammasome proteins which led to a further understanding of ASC oligomerization.