In thermal cracking and collision-induced dissociation (CID) processes, molecules/ions mainly undergo cleavage reactions. In theory, the cleavage reaction is preferred for weak bonds in both processes. The present study investigates the thermal cracking and CID behavior of polar compounds in vacuum residue. By controlling the thermal reaction temperature and collision energy, different degrees of fragmentation were achieved. The molecular composition before and after the cracking process was analyzed through electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR MS). There was a correlation between the reaction temperature and the collision energy for the average carbon number value. Both desulfurization and decarboxylation were also observed in two processes due to the low C-S bond energy and poor stability of carboxylic acid groups. Nevertheless, the two processes still had some differences in reaction selectivity. Polar species tended to be directly dealkylated down to the C1−C5 substituted aromatic core in the CID process, showing a discontinuity in the carbon number vs. double bond equivalence (DBE) distribution for the CID product. On the contrary, the carbon number distribution in the thermal reaction showed a continuously reduced trend. In summary, the CID process can qualitatively reflect the cracking behavior. However, the product structural distribution of the thermal cracking product cannot be fully predicted, especially for sidechain cracking reactions. In addition, the research results can provide a new method to realize the simulation of the thermal cracking without energy and time consumption, so as to guide the selection of the feedstock and optimization of the reaction condition.