Precise detection of ultralow-level antibiotics, such as picomole, in aqueous environments is significant for human health, however, it presents a great challenge to the adsorption capacity and electrocatalytic ability of sensing materials. Here, we used a one-step hydrothermal method to in situ grow spindle-like CoFe-based metal-organic frameworks (MOFs) with a size of about 50 nm in the region of hydrophilic MXene-loading hydrophobic carbon paper. By combining MOFs with abundant adsorption sites and MXene with high conductivity, the problems of adsorption and electrons transfer of ultralow-level antibiotics have been solved, and achieving precise detection of picomole-level antibiotics. As a result, the CoFe-MOFs/MXene/HCP sensing electrode exhibits the ultralow limit of detection with 33 pM and a wide detection range with 0.1 nm-2.0 mM for chloramphenicol (CAP) detection, as well as the designed sensor has excellent anti-interference, reproducibility, and stability. Importantly, the prepared sensing electrode exhibits reliable analytical results for CAP in real water samples, such as bottled water, milk, and urine, indicating that the prepared sensors have a great potential for application in the analysis of antibiotics in real samples.