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Presacral neoplasms are rare retrorectal tumors with highly heterogeneous histogenesis and obscure clinical manifestations. Due to their deep anatomical location and non-specific perianal symptoms, they are frequently misdiagnosed as perianal mimics (benign inflammatory anorectal lesions that mimic presacral tumors clinically), leading to delayed intervention, increased malignant progression risk, and compromised oncological prognosis. The present study aimed to identify core H&E-stained morphological features associated with preoperative misdiagnosis of presacral neoplasms, evaluate their value for lowering preoperative misdiagnosis, and establish a practical pathological diagnostic system for clinical oncological practice. A retrospective diagnostic cohort study was conducted in 112 patients with pathologically confirmed primary presacral neoplasms. H&E sections were independently reviewed by senior pathologists, and logistic regression was applied to identify independent morphological features. The impact of standardized H&E morphological criteria on misdiagnosis rate was quantitatively analyzed. The results identified that three independent H&E morphological features correlated with misdiagnosis risk among presacral neoplasm specimens: specific tumor cell morphology (OR = 6.25, 95% CI:2.48-15.76, P < 0.001), cystic/solid mixed architecture (OR = 5.82, 95% CI:2.31-14.65, P < 0.001), and absence of perianal tissue-specific structures (OR = 5.18, 95% CI:2.05-13.08, P < 0.001). After implementation of the standardized diagnostic criteria, the overall preoperative misdiagnosis rate decreased from 29.5% to 10.2% (P < 0.001), and the biopsy-related misdiagnosis rate dropped from 84.8% to 9.1% (P < 0.001). A representative case of presacral gastrointestinal stromal tumor (GIST) was comprehensively demonstrated with integrated imaging, endoscopic, intraoperative, gross, and H&E pathological features. In conclusion, standardized evaluation based on key H&E morphological features helps lower the preoperative misdiagnosis rate of presacral neoplasms. Standardized interpretation of these indicators significantly reduces misdiagnosis, facilitates early oncological recognition, and improves clinical management efficiency. This strategy is particularly suitable for primary and secondary medical institutions and requires prospective clinical verification.