Background: Broad-spectrum antibiotics are often used for suspected infections in patients with hematologic malignancies due to the risk of severe infections. Although antibiotic use can lead to antimicrobial resistance and microbiome dysbiosis, the effects of antibiotics on the microbiome and resistome in patients with acute myeloid leukemia (AML) undergoing remission induction chemotherapy (RIC) are not well understood. Methods: Various statistical models were utilized to examine the effects of antibiotic administration on the microbiome and resistome over time, as well as differences in AR-infection (ARI) and colonization (ARC) by important CDC-threats in 119 AML patients. Results: A greater number of unique antibiotic classes administered correlated with a loss of unique antibiotic resistance genes (ARGs) (R = −0.39, p = 0.008). Specifically, although a greater number of oxazolidinone administrations was correlated with a greater loss of diversity (R = −0.58, p < 0.001), each additional day of linezolid reduced the risk of ARC by ~30% (HR: 0.663, p = 0.047) and decreased the odds of acquiring genes predicted to confer macrolide (HR: 0.50, p = 0.026) resistance. Conclusions: The number of antibiotic administrations and the types of antibiotics used can influence the risk of antibiotic resistance gene (ARG) expansion and ARC events in AML patients undergoing RIC. While certain antibiotics may reduce microbial diversity, they are not always linked to an increase in ARGs or ARC events.