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Summary: A liquid biopsy is a noninvasive approach for detecting double-stranded circulating tumor DNA (ctDNA) of 90–320 nucleotides in blood plasma from patients with cancer. Most techniques employed for ctDNA detection are time consuming and require expensive DNA purification kits. Electrochemiluminescence resonance energy transfer (ECL-RET) biosensors exhibit high sensitivity, a wide response range, and are promising for straightforward sensing applications. Until now, ECL-RET biosensors have been designed for sensing short single-stranded oligonucleotides of less than 45 nucleotides. In this work, an ECL-RET biosensor comprising graphitic carbon nitride quantum dots was assessed for the amplification-free detection in the blood plasma of DNA molecules coding for the EGFR L858R mutation, which is associated with non-small-cell lung cancer. Following a low-cost pre-treatment, the highly specific ECL-RET biosensor quantified double-stranded EGFR L858R DNA of 159 nucleotides diluted into the blood within a linear range of 0.01 fM to 1 pM, demonstrating its potential for noninvasive biopsies.