Targeting refractory and metastatic non-small cell lung cancer remains a clinical challenge. This study evaluated lichen-derived metabolites-atraric acid (AA), physciosporin (PHY), usnic acid (UA), and atranorin (ATR)-against distinct A549 lung adenocarcinoma sublines (parental WT, chemoresistant/metastatic RSM, and metastatic 19DMS) and colorectal lines (HCT 116, SW 620). Expression of the metastasis regulator KITENIN (VANGL1) was also analyzed across these models. KITENIN mRNA and protein levels were determined by qPCR and Western blotting. Metabolite cytotoxicity was tested by MTT, and anti-invasive capacity was quantified by gelatin-coated Transwell assays. In MTT assays, PHY, UA, and ATR showed dose-dependent toxicity, whereas AA produced negligible cytotoxicity. Importantly, AA, PHY, and ATR significantly suppressed A549 cell invasion (p < 0.001), with AA demonstrating robust anti-invasive efficacy without cell death. KITENIN mRNA levels varied among A549 sublines, while HCT 116 showed high expression. KITENIN protein was detected in A549/WT, A549/RSM, and HCT 116, weak in A549/19DMS, and undetectable in SW 620. Lichen metabolites, particularly atraric acid, attenuate invasion in drug-resistant and metastatic A549 cells without cytotoxicity, supporting their potential as anti-metastatic leads.