Extracellular signal-regulated kinase 1/2 (ERK1/2) is involved in the regulation of the key cellular processes that are essential for the proper functioning of the cell under physiological conditions. Notably, the hyperactivation of ERK1/2 is implicated in oncogenesis and metastatic dissemination across various tumor types, making it an attractive candidate for targeted therapy (TT) through functional inhibition. In intrahepatic cholangiocarcinoma (iCCA), sustained ERK1/2 activation represents one of the major events within the complex signaling network that drives tumor development and progression. In this review, we dissect the biological role of ERK1/2 signaling in iCCA and highlight recent preclinical advances involving selective small-molecule ERK1/2 inhibitors. In vitro and in vivo studies have demonstrated how these inhibitors present effective anti-tumorigenic properties. In particular, PD901 and U0126 effectively reduce iCCA cell proliferation and invasion. Furthermore, Ulixertinib has shown a favorable therapeutic index and encouraging activity in clinical trials involving advanced solid tumors, including iCCA, paving the way for a new therapeutic approach targeting ERK1/2. Nevertheless, the heterogeneous and dynamic molecular landscape of iCCA, often accompanied by drug resistance, presents significant therapeutic challenges. We underscore how targeting the ERK1/2 pathway could represent a cornerstone within a multifaceted therapeutic strategy, fostering the development of personalized treatment approaches and improving clinical outcomes in iCCA patients.