Despite significant advancements in kinase-targeted therapy, the emergence of acquired drug resistance to targets such as KRAS and MEK remains a challenge. Extracellular-regulated kinase 1/2 (ERK1/2), positioned at the terminus of this pathway, is highly conserved and less susceptible to mutations, thereby garnering attention as a crucial therapeutical target. However, attempts to use monotherapies that target ERK1/2 have achieved only limited clinical success, mainly due to the issues of limited efficacy and the emergence of drug resistance. Herein, we present a proof of concept that extracellular-regulated kinase 5 (ERK5) acts as a compensatory pathway after ERK1/2 inhibition in triple-negative breast cancer (TNBC). By utilizing the principle of polypharmacology, we computationally designed SKLB-D18, a first-in-class molecule that selectively targets ERK1/2 and ERK5, with nanomolar potency and high specificity for both targets. SKLB-D18 demonstrated excellent tolerability in mice and demonstrated superior in vivo anti-tumor efficacy, not only exceeding the existing clinical ERK1/2 inhibitor BVD-523, but also the combination regimen of BVD-523 and the ERK5 inhibitor XMD8-92. Mechanistically, we showed that SKLB-D18, as an autophagy agonist, played a role in mammalian target of rapamycin (mTOR)/70 ribosomal protein S6 kinase (p70S6K) and nuclear receptor coactivator 4 (NCOA4)-mediated ferroptosis, which may mitigate multidrug resistance.