New Inquiry-Based Learning (NIBL) was developed to improve students’ multiple higher-order thinking skills (MHOTS), such as thinking critically, analytically, creatively, and practically (CACP). This study aimed to examine the increase of students’ MHOTS ability, their perceptions of the NIBL model, and the contribution of the NIBL model to the learning outcomes.  A quasi-experiment of the nonequivalent control group design was implemented in this study. Research subjects were university students majoring in chemistry education and enrolling in the Organic Chemistry course. The experiment and the control groups consisted of 34 and 32 students, respectively. The collected data were analyzed by using t-test and ANCOVA procedures. N-Gain scores were calculated to measure the differences in the increase in learning outcomes. Eta square values measured the contribution of NIBL. The results of this study revealed that there were differences in the learning outcomes of the experiment and control group. The CACP thinking skills and the mastery of organic chemistry concepts of the experiment group increased significantly. The N-Gain scores of practical thinking skills aspect were on medium category, and for critical, analytical, and creative thinking, as well as for mastery of organic chemistry concepts were on high categories. For the control group, the N-Gain scores of all categories were on low or medium categories. The NIBL model effectively improved the prospective chemistry teachers’ M-HOTS in terms of CACP thinking skills and contributed significantly to the increase in the students’ mastery of organic chemistry concepts.