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Simple Summary: B-cell lymphoma (BCL) represents the most common hematological malignancy in dogs and, despite the current chemotherapeutic standard, is generally characterized by poor outcome, highlighting the importance of new drug development. The medical approach to cancer has been revolutionized by the advent of targeted therapies, consisting in targeting specific molecules crucial for malignant cells growth and proliferation. Myc is a transcription factor dysregulated in many cancers, including canine BCL (cBCL). For several reasons, directly targeting Myc remains challenging, but alternative routes have been explored. In our study, we developed and tested on two in vitro models of cBCL a dual approach to indirectly target Myc using two drugs (BI2536 and MZ1). After confirming the specificity of the drugs to their main targets, we observed that both molecules affected the cell viability, individually and in combination. Furthermore, BI2536, alone and in combination with MZ1, induced significant transcriptomic changes in cBCL cell lines, primarily affecting MYC target genes and genes involved in the cell cycle regulation. Our study offers valuable insights into the mechanisms of action of BI2536 and MZ1 in cBCL cell lines and highlights their potential as targeted therapies for this cancer subtype. B-cell lymphomas (BCL) is the most frequent hematological cancer in dogs. Treatment typically consists of chemotherapy, with CHOP-based protocols. However, outcome remains generally poor, urging the exploration of new therapeutic strategies with a targeted approach. Myc transcription factor plays a crucial role in regulating cellular processes, and its dysregulation is implicated in numerous human and canine malignancies, including canine BCL (cBCL). This study aims to evaluate the efficacy of indirectly inhibiting Myc in cBCL using BI2536 and MZ1 compounds in two in vitro models (CLBL-1 and KLR-1201). Both BI2536 and MZ1, alone and combined, affected cell viability in a significant concentration- and time-dependent manner. Western Blot revealed an upregulation of PLK1 expression in both cell lines upon treatment with BI2536, in association with a reduction in c-Myc protein levels. Conversely, MZ1 led to a decrease in its primary target, BRD4, along with a reduction in c-Myc. Furthermore, BI2536, both alone and in combination with MZ1, induced larger transcriptomic changes in cells compared to MZ1 alone, primarily affecting MYC target genes and genes involved in cell cycle regulation. These data underscore the potential role of Myc as therapeutic target in cBCL, providing a novel approach to indirectly modulate this molecule. [ABSTRACT FROM AUTHOR]