According to WHO, cancer has become the leading cause of death, accounting for 10 million deaths in 2020. The only effective way to fight cancer is early detection and effective treatment. Detection of circulating tumor cells (CTCs) from blood is one of the ways of early detection as they are detectable even before tumors. The conventional labeling method primarily targets CTCs based on specific surface proteins, limiting its applicability to various types of cancer cells. Introducing surface molecules through surface glycoengineering, as presented in this study, offers an innovative approach, with these molecules present in significantly greater numbers than naturally occurring surface proteins. This method allows for the targeting of tumors metabolically and enables the detection of various cancer cell types. This study also compares the proposed detection technique with the conventional EpCAM-based method. It showcases its effectiveness in tagging three different cancer cell lines: the EpCAM-negative cervical cancer cell (HeLa), the weakly EpCAM-positive triple-negative breast cancer cell (MDA-MB-231), and the strongly EpCAM-positive breast cancer cell (MCF7). Importantly, this approach is shown to be independent of naturally occurring cell surface proteins and widely applicable, yielding significantly higher tagging efficiency and average fluorescence signal compared to the established anti-EpCAM-FITC-based method. Due to the rarity of CTCs in blood, there is a need to choose a single-cell analysis platform. Hence, an opto-microfluidic platform has been developed for the demonstration of this detection. The proposed technique is then utilised for the detection of CTCs in metastatic cancer patients’ blood. The current work provides a new strategy for detecting cancer cells in the blood that can find potential applications in both fundamental research and clinical studies involving CTCs as well as in single-cell sequencing.