Chinese universities have been conducting a variety of sexuality education programs, including a sexuality curriculum (SC) to increase sexual and reproductive health (SRH) knowledge and improve sexual attitudes and practices among college students. However, little is known regarding the effect of SC on students' sexual attitudes and behaviors. The purpose of this study was to evaluate the effect of SC on SRH knowledge, sexual attitudes, and practices among college students of Shandong University. To assess these issues, an online cross-sectional survey was conducted via a WeChat applet. Four hundred and forty-nine freshmen were recruited from Shandong University, including 209 students with SC and 240 students without SC. We assessed their SRH knowledge, sexual attitude, and practice. We found that 15.8% engaged in sexual activities, while 59.2% had viewed nonscientific books or videos describing sexual behavior within the past 2 weeks. Regarding the initial source of their SRH information, 65.9% taught themselves through reading or viewing SRH content in the media, and 46.8% participated in school lectures on SRH, while only 31.2% of the participants discussed SRH matters with their parents. As compared with students without SC, students with SC had significantly greater total scores with regard to reproductive health knowledge (P < 0.001) and sexual health knowledge (P < 0.001). Students without SC showed a significant degree of prejudice against sexually transmitted disease patients and were more resistant to interact with acquaintances infected with human immunodeficiency virus (P < 0.001). Exposure to a school-based SC had a beneficial effect on increasing the SRH knowledge of these students as well as mitigating risky sexual attitudes and behaviors.