Nanoplastic contamination is an emerging environmental concern worldwide. In particular, sulfate anionic surfactants often appear along with nanosized plastic particles in personal care products, suggesting that sulfate-modified nanosized polystyrene (S-NP) may occur, remain, and spread into the environment. However, whether S-NP adversely affects learning and memory is unknown. In this study, we used a positive butanone training protocol to evaluate the effects of S-NP exposure on short-term associative memory (STAM) and long-term associative memory (LTAM) in Caenorhabditis elegans. We observed that long-term S-NP exposure impairs both STAM and LTAM in C. elegans. We also observed that mutations in the glr-1, nmr-1, acy-1, unc-43, and crh-1 genes eliminated the STAM and LTAM impairment induced by S-NP, and the mRNA levels of these genes were also decreased upon S-NP exposure. These genes encode ionotropic glutamate receptors (iGluRs), cyclic adenosine monophosphate (cAMP)/Ca2+ signaling proteins, and cAMP-response element binding protein (CREB)/CRH-1 signaling proteins. Moreover, S-NP exposure inhibited the expression of the CREB-dependent LTAM genes nid-1, ptr-15, and unc-86. Our findings provide new insights into long-term S-NP exposure and the impairment of STAM and LTAM, which involve the highly conserved iGluRs and CRH-1/CREB signaling pathways.