Tumors are complex microenvironments in which uncontrolled cell proliferation alters biochemical pathways as well as the physical and electrical properties of tissues. Electrochemotherapy (ECT) exploits electroporation-induced transient increases in cell membrane permeability to enhance intracellular delivery of chemotherapeutic agents. Electroporation is associated with a reduction in tissue electrical resistance due to aqueous pore formation, influenced by electric field intensity, pulse number, and tissue architecture. This study aimed to evaluate changes in tumor electrical resistance during ECT in 39 cats with squamous cell carcinoma (SCC) and to investigate potential correlations between resistance reduction and therapeutic response. Lesions were located on the nasal planum or eyelids and staged as T1–T4N0M0. Tumor electrical resistance (Ω) was recorded in real time for each pulse during all ECT sessions using a veterinary-modified clinical electroporator with integrated resistance-measurement software. Resistance values ranged from 600 to 4900 Ω. Statistical analysis revealed a significant decrease in resistance across sessions and pulses. Resistance was higher in eyelid lesions compared with nasal planum tumors and lower in cats achieving complete response. Additionally, resistance varied significantly among tumor grading, with a significant interaction between tumor stage and localization. In conclusion, tumor electrical resistance decreases during ECT in feline SCC, and lower resistance values are associated with improved local tumor control. Real-time resistance monitoring may represent a non-invasive surrogate marker of effective electroporation and treatment adequacy.