In this work, the thermal cracking process of seventeen (17) vacuum residues from Colombian crude oils is studied. Cracking tests are carried out in a batch microreactor at 390, 410, 420, and 430 °C, during 60 min of reaction and in an inert atmosphere with nitrogen. The quality of the vacuum residues and its products, obtained under thermal cracking conditions, is determined by thermogravimetric analysis and proton nuclear magnetic resonance (1H NMR) spectroscopy, whereas the yield of liquid products is calculated via simulated distillation following the ASTM D7169 standard. The thermogram trends show three zones, one in the range of 100–300 °C, where few chemical changes are observed, one between 300 and 550 °C, where the greatest formation of volatile compounds occurs, and the third, in the range of 550–900 °C, where the mass loss decreases to a constant average weight of 14.8% (±6.3%). In contrast, the fractional conversion curves show two reactivity zones corresponding to the vaporization and thermal cracking stages, with activation energies ranging between 53.9–97.7 and 132.2–192.5 kJ/mol, respectively. It is observed that the activation energy in the cracking zone increases as the vacuum residues become heavier. The tendency of the distillation curves for the liquid products shows a significant increase in the 525 °C fraction yield from each vacuum residue, with the increasing reactivity temperature of the thermal cracking. The analysis of the average molecular parameters via 1H NMR confirms that the reactivity and product yield vary according to the complexity of the molecular structure in the vacuum residues. On the other hand, the results of this research contribute to the development of a methodology of reactivity and compositional characterization by using 1H NMR spectroscopy and multivariate models to evaluate the thermal cracking effect of vacuum residues on a laboratory scale.