Abstract Background Let-7 microRNAs (miRNAs) may contribute to neurodegeneration, including Alzheimer's disease (AD), but, they were not investigated in Streptozotocin (STZ)-induced AD. Letrozole increases the expression of Let-7 in cell lines, with conflicting evidence regarding its effects on memory. This study examined Let-7 miRNAs in STZ-induced AD, their correlation with memory and hyperphosphorylated Tau (p-Tau) and the effects of Letrozole on them. Methods Seven groups of adult Sprague Dawley rats were used: Negative control, Letrozole, Letrozole Vehicle, STZ (with AD induced by intracerebroventricular injection of STZ in artificial cerebrospinal fluid (aCSF)), CSF Control, STZ + Letrozole (STZ-L), and CSF + Letrozole Vehicle. Alternation percentage in T-maze was used as a measure of working memory. Let-7a, b and e and p-Tau levels in the hippocampus were estimated using quantitative real-time reverse transcription–polymerase chain reaction (qRT–PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results Significant decreases in alternation percentage and increase in p-Tau concentration were found in the STZ, Letrozole and STZ-L groups. Expression levels of all studied microRNAs were significantly elevated in the Letrozole and the STZ-L groups, with no difference between the two, suggesting that this elevation might be linked to Letrozole administration. Negative correlations were found between alternation percentage and the levels of all studied microRNAs, while positive ones were found between p-Tau concentration and the levels of studied microRNAs. Conclusions This study shows changes in the expression of Let-7a, b and e miRNAs in association with Letrozole administration, and correlations between the expression of the studied Let-7 miRNAs and both the status of working memory and the hippocampal p-Tau levels. These findings might support the theory suggesting that Letrozole aggravates pre-existing lesions. They also add to the possibility of Let-7’s neurotoxicity.