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Abstract Objectives To assess the cost-effectiveness of cetuximab in combination with chemotherapy fluorouracil, oxaliplatin, and leucovorin (FOLFOX) or fluorouracil, irinotecan and leucovorin (FOLFIRI) compared to standard chemotherapy alone as a first-line treatment for metastatic colorectal cancer (mCRC) with positive KRAS wild type patients in Indonesia. Methods A cost-utility analysis applying Markov model was constructed, with a societal perspective. Clinical evidence was derived from published clinical trials. Direct medical costs were gathered from hospital billings. Meanwhile, direct non-medical costs, indirect costs, and utility data were collected by directly interviewing patients. We applied 3% discount rate for both costs and outcomes. Probabilistic sensitivity analysis was performed to explore the model’s uncertainty. Additionally, using payer perspective, budget impact analysis was estimated to project the financial impact of treatment coverage. Results There was no significant difference in life years gained (LYG) between cetuximab plus FOLFOX/FOLFIRI and chemotherapy alone. The incremental QALY was only one month, and the incremental cost-effectiveness ratio (ICER) was approximately IDR 3 billion/QALY for cetuximab plus chemotherapy. Using 1–3 GDP per capita (IDR 215 million or USD 14,350) as the current threshold, the cetuximab plus chemotherapy was not cost-effective. The budget impact analysis resulted that if cetuximab plus chemotherapy remain included in the benefits package under the Indonesian national health insurance (NHI) system, the payer would need more than IDR 1 trillion for five years. Conclusions The combination of cetuximab and chemotherapy for mCRC is unlikely cost-effective and has a substantial financial impact on the system.