Purpose Oral oncolytics have improved survival in hematological cancers like chronic myeloid leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, and multiple myeloma; however, it is unclear of the extent to which initiating these treatments might impact adherence to oral therapies for pre-existing comorbid chronic conditions. Methods Adults diagnosed with and prescribed oral oncolytics for chronic myeloid leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, or multiple myeloma between 2013 and 2016 and with continuous eligibility six months before and after oral oncolytic initiation were identified from the Truven Health MarketScan databases. Among those identified, patients with pre-existing diabetes, hypertension, and/or hyperlipidemia with ≥1 fill for oral comorbid therapies were selected. Adherence to oral oncolytics and comorbid therapies was measured using the proportion of days covered metric. Wilcoxon signed-rank tests assessed changes in adherence for comorbid therapies after initiation of an oral oncolytic. Unadjusted difference-in-difference models assessed the impact of adherence to oral oncolytics on changes in adherence to comorbid therapies. Results Significant reductions in adherence after oncolytic initiation were observed across the comorbid therapies and were highest for patients taking lipid-lower agents (10.7–15.6%). Unadjusted difference-in-difference models revealed consistent and significantly lower reductions in adherence for those taking antihypertensives (chronic myeloid leukemia: p = 0.03; chronic lymphocytic leukemia/small lymphocytic lymphoma: p = 0.007; multiple myeloma: p = 0.09) and adherent to oral oncolytics. Conclusion Initiation of oral oncolytics may negatively impact adherence to oral therapies for chronic comorbid conditions, necessitating the need for medication management strategies to help patients adhere to their entire medication regimen.