Periplocin, a tumor-inhibitory compound derived from Cortex periploca, was investigated for its mechanisms of action and therapeutic potential against human papillary thyroid carcinoma cell proliferation. BCPAP/TPC-1 cells were treated with periplocin ± necrostatin-1 (a necroptosis inhibitor) or Z-Val-Ala-Asp(OMe)-fluoromethylketone (an apoptosis inhibitor). Cell proliferation was assessed using the cell counting kit 8/real-time cell analysis assay. Necrotic morphology was quantified using Hoechst 33,342/propidium iodide (PI) staining (PI⁺ rate), and apoptosis/necroptosis pathways were analyzed using Annexin V-FITC/PI flow cytometry. RNA-seq was conducted to compare the transcriptomes of periplocin-treated and untreated TPC-1 cells. The key proteins (phosphorylated mixed lineage kinase domain-like protein [p-MLKL], phosphorylated receptor-interacting protein kinase-3 [p-RIP3], IL6, IL1A, and death receptor 4 [DR4]) were validated by western blotting. In vivo, TPC-1 xenografts from BALB/c nude mice were evaluated for tumor growth, necrosis (PI staining), and expression of protein markers (proliferating cell nuclear antigen, p-MLKL, and p-RIP3) via immunohistochemistry. Periplocin suppressed the growth of BCPAP and TPC-1 thyroid carcinoma cells via concentration-dependent necroptosis. Necrostatin-1 co-treatment reduced PI⁺ cells and necrotic morphology (high Hoechst/PI staining; P < 0.05), confirming necroptosis dependence. Mechanistically, periplocin activated RIP3/MLKL signaling and damage-associated molecular patterns, whereas DR4 knockdown (si-DR4) attenuated p-MLKL expression (P < 0.01), indicating DR4-mediated pathway activation. In vivo, periplocin reduced TPC-1 xenograft volume (P < 0.01), weight, and proliferation (decreased proliferating cell nuclear antigen⁺ cells; P < 0.05), while elevating p-RIP3/p-MLKL (P < 0.01) and PI⁺ necrosis (P < 0.01). Periplocin selectively induces DR4-dependent necroptosis via RIP3/MLKL activation, providing the first evidence of necroptosis induction in papillary thyroid carcinoma. These findings suggest that periplocin is a promising therapeutic candidate, particularly for tumor necrosis factor-related apoptosis-inducing ligand-resistant papillary thyroid carcinoma that evades apoptosis.