La-related protein 1 (LARP1) is an RNA-binding protein and downstream effector of mTOR and CDK9 signaling that regulates the translation of 5’-TOP mRNAs. While elevated LARP1 expression has been linked to poor prognosis in acute myeloid leukemia (AML), its mechanistic role remains unclear. Using CRISPR/Cas9-mediated LARP1 knockout and transcriptomic, translatomic, proteomic, and metabolomic analyses, we investigated LARP1’s role in AML. LARP1 loss impaired proliferation, clonogenicity, and tumor growth in xenografts, and enhanced sensitivity of AML cells to azacitidine and cytarabine. Polysome profiling and RNA sequencing revealed that LARP1 modulates a distinct set of transcripts involved in mitochondrial function, amino acid metabolism, and cell cycle regulation, independently of mTOR or CDK9. Proteomics analysis uncovered additional effects on immune signaling, lysosomal pathways, and protein stability, including changes not evident at the RNA level. Metabolomic profiling showed broad reprogramming of the arginine and creatine metabolic pathways and depletion of pyrimidine biosynthesis intermediates. Cytidine deaminase, a known resistance factor, was downregulated at both the transcript and protein levels upon LARP1 loss. These findings define LARP1 as a key integrator of translational regulation and metabolic control in AML, supporting leukemic cell survival and promoting drug resistance. Targeting LARP1 may uncover vulnerabilities not addressed by current antileukemia therapies.