Octreotide (OCT) is widely used for the treatment of acromegaly, neuroendocrine tumors such as gastrinoma, and ruptured esophagogastric variceal bleeding in clinical. However, due to the short half-life of octreotide, the patients need frequent dosing in the treatment of diseases requiring long-term medication such as acromegaly, which leads to poor compliance. Therefore, it is urgent to develop a long-acting sustained-release formulation that can improve patient compliance. And since octreotide is a small molecule peptide drug that is extremely soluble in water, it tends to escape to the external aqueous phase during the preparation of microspheres, resulting in low drug loading and encapsulation efficiency. In this study, HIP-OCT complexes were prepared by hydrophobic ion-pairing (HIP) method. The effects of charge ratio, pH value, and temperature on the binding efficiency of the complexes were investigated, and the water solubility and dissociation of the complexes were observed. The sodium dodecyl sulfate-octreotide (SDS-OCT) with 93.77% binding efficiency, 9.31% water solubility, and 92.10% dissociation was screened as the optimal complex from the four HIP-OCT complexes. Due to the formation of HIP complexes, the hydrophilicity of OCT was changed and the difficulty of OCT encapsulation in double emulsion method was overcome. The SDS-OCT complex microspheres were prepared by the O1/O2/W double emulsion method combined with the premix membrane emulsification technique. Finally, the uniform SDS-OCT microspheres with particle size of 28.02 μm, Span value of 0.776, drug loading efficiency of 6.51%, and encapsulation efficiency of 72.00% were prepared under the negative pressure solidification, drug concentration of 80 mg/mL and poly(D,L-lactic-co-glycolic acid) (PLGA) concentration of 200 mg/mL. The in vitro accelerated release of the prepared SDS-OCT complex microspheres was basically in line with the trend of zero-level release, and the cumulative release was close to 100%. In vivo pharmacodynamic experiments showed that the microspheres had stable and long-term sustained release within one month.