This study examined the effect of design-based science instruction (DBSI) on sixth grade students' science achievement, as well as their development in relation to science process skills. 213 sixth grade students from three public schools participated in the study. A pilot was conducted in the unit of Systems of the Human Body and the main study was carried out during the units of Force and Motion, Matter and Heat, and Sound and its Properties. While the experimental group was taught through the DBSI method, the control group was taught in accordance with the inquiry-based curriculum-oriented science instruction. Mixed between-within subjects ANOVA showed that at the end of the treatment, the mean scores of the experimental group concerning all dependent variables were found statistically higher than those of the control group. The achievement scores of both groups increased over time; however, the effect size values indicated that the increase in the achievement scores in the experimental group was greater than that in the control group. Regarding the science process skills, while scores of the students in the experimental group increased over time, no significant change occurred in the control group. The results showed that the DBSI exerts a positive influence on middle school students related to their science achievement and science process skills. Based on the findings, suggestions were made for science teachers and researchers.