The quantification of harmful elements in cannabis is a relevant analytical task that requires metrological tools to ensure the reliability of the measurement results. This work reports the preparation and characterization of a certified reference material (CRM) for toxic elements—arsenic (As), cadmium (Cd), and lead (Pb)—in pulverized, lyophilized cannabis leaf tissue. To prepare the CRM INM-040-1, a portion of dried ground cannabis vegetal material was spiked with the elements at mass fraction values close to the levels of interest in relevant regulations for this kind of matrix: 0.34 mg/kg for arsenic, 0.34 mg/kg for cadmium, and 0.66 mg/kg for lead. The elements were quantified by inductively coupled plasma mass spectrometry (ICP-MS) in combination with graphite furnace atomic absorption spectroscopy (GF-AAS, for cadmium and lead) or hydride generation atomic absorption spectroscopy (HG-AAS, for arsenic). The analytical calibration was done by gravimetric standard addition for ICP-MS and GF-AAS, while bracketing calibration was used for HG-AAS. Furthermore, internal standard correction was used during ICP-MS measurements. The analytical methods were validated to demonstrate their fitness for purpose. The preparation variables of the CRM (particle size, drying treatment, and spiking conditions) were studied to improve the homogeneity of the CRM. The mass fraction of the toxic elements was certified with relative standard uncertainties ranging from 4.2 to 6.9%. The uncertainty contributions considered were the elements’ mass fraction measurements, the between-methods bias, the (in)homogeneity of the production batch, and the (in)stability under transport and storage conditions. This new CRM constitutes a useful tool for the laboratories assessing the harmlessness of cannabis materials, promoting humans’ safety and regulatory compliance within the medicinal cannabis industry. Graphical Abstract