A series of in vitro trials was conducted to evaluate the influence of limestone, dicalcium phosphate, phytase, and the digestion phase on Ca and P solubility. Experimental samples were arranged as a 2 × 2 × 2 × 2 factorial and contained corn (experiment 1) or soybean meal (experiment 2) plus limestone, dicalcium phosphate, phytase, and all combinations. Calcium and available P in the samples were maintained at 1.0% with limestone and 0.45% with dicalcium phosphate, respectively. Phytase was added to the samples at 1,000 FTU/kg. Samples were exposed to a 2-step in vitro digestion assay to simulate the gastric and the small intestinal (SI) phases of digestion. In experiment 1, dicalcium phosphate improved (P ≤ 0.05) P solubility in the gastric phase, which did not change in the SI phase, except when phytase was supplemented, which reduced (P ≤ 0.05) P solubility in the SI phase. The small amount of Ca present in corn is highly soluble, but limestone, dicalcium phosphate, or phytase reduced (P ≤ 0.05) Ca solubility in the gastric phase. Solubility was further reduced (P ≤ 0.05) in the SI phase in the presence of limestone. In experiment 2, P was more soluble (P ≤ 0.05) in the presence of limestone, dicalcium phosphate, or phytase in the gastric phase and compared with P solubility in the SI phase. Calcium solubility was reduced (P ≤ 0.05) in the SI phase compared with the gastric phase, except when dicalcium phosphate or limestone was supplemented. In conclusion, P and Ca solubility were influenced by the change in pH between the gastric and SI phases, differences in diet composition, and the Ca:P ratio. Limestone, dicalcium phosphate, and phytase increased P solubility in the gastric phase and reduced P solubility in the SI phase. Phytase had more of an effect on P and Ca solubility in soybean meal than in corn, and this is possibly a result of the high amount of phytate in soybean meal.