With the limited but ongoing usage of perfluorooctane sulfonate (PFOS), the health effects of both PFOS and its alternatives are far from being understood. Long-term potentiation (LTP) was evaluated in rats after exposure to PFOS and its alternatives, aiming to provide some evidence about their potential to affect cognitive ability. Different dosages of PFOS and alternative chemicals, including perfluorohexane sulfonate (PFHxS), perfluorobutane sulfonate (PFBS) and chlorinated polyfluorinated ether sulfonate (Cl-PFAES), were given to rats via acute intracerebroventricular injection. The field excitatory postsynaptic potential (fEPSP) amplitude of the input/output functions, paired-pulse facilitations, and LTP in vivo were recorded. PFOS and its alternatives inhibited LTP in varying degrees, without significant effects on the normal synaptic transmission. In addition, PFHxS and Cl-PFAES exhibited comparable potential to PFOS in disturbing LTP. The results suggested that acute exposure to PFOS and its alternatives impaired the synaptic plasticity by a postsynaptic rather than a presynaptic mechanism. Besides, the fEPSP amplitude of the baseline was reduced by Cl-PFAES but not by other compounds, indicating that Cl-PFAES might act in a different mode. Providing some electrophysiological evidence and the potential mechanism of the neurotoxicity induced by PFOS and its alternatives, the present study addresses further evaluation of their safety and health risks.