Background Exposure to anesthesia leads to extensive neurodegeneration and long‐term cognitive deficits in the developing brain. Caenorhabditis elegans also shows persistent behavioral changes during development after exposure to anesthetics. Clinical and rodent studies have confirmed that altered expression of the regulators of G protein signaling (RGS) in the nervous system is a factor contributing to neurodegenerative and psychological diseases. Evidence from preclinical studies has suggested that RGS controls drug‐induced plasticity, including morphine tolerance and addiction. This study aimed to observe the effect of propofol exposure in the neurodevelopmental stage on learning and memory in the L4 stage and to study whether this effect is related to changes in rgs‐3 expression. Methods Caenorhabditis elegans were exposed to propofol at the L1 stage, and learning and memory abilities were observed at the L4 stage. The expression of rgs‐3 and the nuclear distribution of EGL‐4 were determined to study the relevant mechanisms. Finally, RNA interference was performed on rgs‐3‐expressing cells after propofol exposure. Then, we observed their learning and memory abilities. Results Propofol time‐ and dose‐dependently impaired the learning capacity. Propofol induced a decline in non‐associative and associative long‐term memory, rgs‐3 upregulation, and a failure of nuclear accumulation of EGL‐4/PKG in AWC neurons. Inhibition of rgs‐3 could alleviate the propofol‐induced changes. Conclusion Inhibition of the expression of rgs‐3 alleviated propofol‐induced learning and memory deficits in Caenorhabditis elegans.