A new series of structurally diverse indole–1,2,4-triazole derivatives was designed and synthesized through a thiolated triazole intermediate derived from indole-3-propionic acid. The final compounds, including S-acetamide, bis-indolyl, triazolothiadiazole, and triazolothiadiazine analogues (3–8), were confirmed by NMR, IR, MS, and elemental analysis. Their cytotoxicity was tested against breast (MCF-7), colon (HCT-116), and liver (HepG2) cancer cell lines, alongside normal BJ-1 fibroblasts, using the LDH assay. Several compounds, especially 3, 6b, 7a, 7c, and 8a,b showed potent and selective antiproliferative effects on MCF-7 and HCT-116 cells with IC50 values between 2.3 and 3.0 μM, outperforming doxorubicin nearly twofold under the same conditions. Mechanistic studies revealed a significant decrease in phosphorylated ERK (pERK) protein levels in MCF-7 cells, with compound 3b showing the strongest inhibition (3.499 ± 0.21 pg/mL), consistent with its IC50 (2.3 μg/mL). Molecular docking supported the strong binding affinity of 3b within the ERK active site (−9.0 kcal/mol), involving hydrogen bonding and hydrophobic interactions. In silico ADMET predictions confirmed favorable drug-likeness, oral bioavailability, and pharmacokinetic safety for this compound. Overall, compound 3b emerges as a promising lead for ERK-targeted anticancer drug development, supported by combined synthetic, biological, and computational evidence.