The photoluminescence-based detection of circulating tumor cells (CTCs) can offer the development of rapid, simple, and sensitive techniques for the screening of cancer at early stages as well the monitoring of therapy progression. The present work reports the application of a photoluminescent composite of Terbium based metal–organic framework (Tb-BTC MOF) with L-cysteine conjugated molybdenum disulphide (MoS2) nanosheets for the highly sensitive immunosensing of HepG2 cells. The formation of the above composite facilitates the achievement of a highly fluorescent, large surface area material with abundant carboxyl functionality. This novel composite has been immobilized with the anti-EpCAM antibodies to form the desired immunosensor for HepG2 cells. After spectroscopic and morphological characterizations, the antibody immobilized Tb-BTC/MoS2 bioprobe (Ab/Tb-BTC/MoS2) has been investigated for the sensing of HepG2 cells (10–1000 cells). Based on the PL quenching mechanism, the above bioprobe has delivered a broad range analysis with a low limit of detection (8 cells). The Ab/Tb-BTC/MoS2 bioprobe is also found selective toward other possible interferants, such as HEK cells, bovine serum albumin, immunoglobin G, and glucose.