In bone tissue engineering, three-dimensional (3D) scaffolds are often designed to have adequate modulus while taking into consideration the requirement for a highly porous network for cell seeding and tissue growth. This article presents the design optimization of 3D scaffolds made of poly(lactic-co-glycolic) acid (PLGA) and nanohydroxyapatite (nHA), produced by thermally induced phase separation (TIPS). Slow cooling at a rate of 1 degrees C/min enabled a uniform temperature and produced porous scaffolds with a relatively uniform pore size. An I-optimal design of experiments (DoE) with 18 experimental runs was used to relate four responses (scaffold thickness, density, porosity, and modulus) to three experimental factors, namely the TIPS temperature (-20, -10, and 0 degrees C), PLGA concentration (7%, 10%, and 13% w/v), and nHA content (0%, 15%, and 30% w/w). The response surface analysis using JMP (R) software predicted a temperature of -18.3 degrees C, a PLGA concentration of 10.3% w/v, and a nHA content of 30% w/w to achieve a thickness of 3 mm, a porosity of 83%, and a modulus of similar to 4 MPa. The set of validation scaffolds prepared using the predicted factor levels had a thickness of 3.05 +/- 0.37 mm, a porosity of 86.8 +/- 0.9%, and a modulus of 3.57 +/- 2.28 MPa. POLYM. ENG. SCI., 59:1146-1157 2019. (c) 2019 Society of Plastics Engineers