Salmon calcitonin phospholipid complex loaded-solid lipid nanoparticles (sCT-PC-SLNs) were prepared from Salmon calcitonin phospholipid complex (sCT-PC) by a film dispersion method. The formulation was optimized by the Box-Behnken response surface design using quality properties such as particle size, polydispersity index (PDI), zeta potential value, entrapment efficiency (EE), and drug loading capacity (DL). The relative bioavailability of different dosage forms of salmon calcitonin (sCT) were calculated separately for plasma calcium percentage of SD female rats after subcutaneous injection and colonic administration. The results show that each dosage form offers reduced plasma calcium levels after colonic administration, except for blank loaded-solid lipid nanoparticles (SLN). The relative bioavailability (0.32 ± 0.17%) for sCT-PC-SLN is twice as high as that of aqueous sCT solution (0.16 ± 0.03%), as well as values for Salmon calcitonin loaded-solid lipid nanoparticles (sCT-SLN) (0.15 ± 0.01%); these results are statistically significant. Compared to SLN, uptake of sCT in a rat colon can be greatly improved by phospholipid complex loaded-solid lipid nanoparticles (PC-SLN). The new dosage form developed here overcomes the low EE of the water-soluble drug, enhances the EE of SLN, and reduces the degradation of gastrointestinal enzymes due to its encapsulation in lipids.