<p>This study aimed to compare the safety and efficacy of two target-controlled infusion (TCI) concentrations of propofol for sedation during cranial functional magnetic resonance imaging (fMRI) in children with autism spectrum disorder (ASD). A total of 120 preschool children with ASD scheduled for fMRI between January 2021 and July 2023 were enrolled and randomized into two groups: a low-concentration group (2.0&#xa0;µg/mL, <i>n</i> = 60) and a high-concentration group (2.5&#xa0;µg/mL, <i>n</i> = 60). Vital signs, sedation parameters, and adverse events were meticulously recorded to assess outcomes. The first-time sedation success rate was high and comparable between the 2.0 group and the 2.5 group (91.67% vs. 96.67%, <i>p</i> = 0.439). However, the 2.5 group demonstrated a significant reduction in mean systolic blood pressure (<i>p</i> = 0.001). While the overall incidence of adverse events was not significantly different, respiratory and circulatory depression events were less frequent in the 2.0 group. Furthermore, the 2.0 group required a significantly lower maintenance dose of propofol (<i>p</i> &lt; 0.001), experienced a shorter recovery time (<i>p</i> = 0.042), and had a smoother emergence profile. In conclusion, a propofol TCI concentration of 2.0&#xa0;µg/mL is effective and safe for fMRI sedation in children with ASD and is clinically preferable to 2.5&#xa0;µg/mL due to a more stable hemodynamic profile, reduced drug requirement, and faster, smoother recovery.</p><p><b>Trial registration</b>: ChiCTR2100050071.</p>