Background: Lung adenocarcinoma (LUAD) continues to be the primary contributor to cancer mortality. Macropinocytosis is a bulk nutrient uptake pathway known to support tumor growth in various cancers, but its functional role and molecular effectors in LUAD cell malignant phenotypes remain unclear. KCNH1 has been reported to modulate progression in multiple types of cancer, yet it has never been linked to macropinocytosis. This study aims to investigate whether macropinocytosis enhances LUAD cell proliferation, migration, and invasion and to identify its key downstream targets. Methods: Two LUAD cell lines, NCI-H358 (KRAS-G12C mutant) and NCI-H1975 (KRAS wild-type), were used. For pharmacological inhibition, cells were treated with 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) (25 μM, 24 h) or dimethyl sulfoxide (DMSO) control. For genetic manipulations, CRISPR/Cas9 knockout and lentiviral overexpression were established, with wild-type (WT) cells and empty vector as controls. Functional effects on proliferation [Cell Counting Kit-8 (CCK-8)], apoptosis (flow cytometry), migration (wound healing), and invasion (Transwell) were evaluated. Transcriptomic changes were analyzed by RNA-sequencing (RNA-seq), with candidate gene expression validated by quantitative real-time polymerase chain reaction (qPCR) and Western blot. Dual-luciferase reporter assay was performed to assess KCNH1 promoter activity. The involvement of the AKT signaling pathway was examined by Western blot. Clinical relevance was examined using The Cancer Genome Atlas (TCGA) database. Results: Inhibition of macropinocytosis significantly reduced the invasion (PKCNH1 as a commonly downregulated target upon EIPA treatment. Dual-luciferase reporter assay confirmed that EIPA treatment directly reduced KCNH1 promoter activity, indicating transcriptional regulation by macropinocytosis. Further experiments established a unidirectional regulatory axis: KCNH1 expression was positively regulated by macropinocytosis at both the mRNA and protein levels, whereas genetic modulation of KCNH1 did not alter macropinocytic activity. Functionally, overexpression of KCNH1 enhanced malignant phenotypes and conferred partial resistance to EIPA, while its knockout suppressed proliferation, migration, and invasion. Mechanistically, KCNH1 modulated AKT phosphorylation, and this pathway mediated its effects on LUAD cell malignant phenotypes. TCGA database analysis revealed elevated KCNH1 expression in LUAD tumors relative to normal tissues, suggesting potential clinical relevance. Conclusions: This study demonstrates that macropinocytosis enhances LUAD cell proliferation, migration, and invasion primarily through the transcriptional upregulation of KCNH1. KCNH1 functions as a crucial downstream effector, mediating the pro-tumorigenic effects of macropinocytosis at least in part via AKT phosphorylation. These findings identify the macropinocytosis-KCNH1 axis as a potential therapeutic target for LUAD.