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<b>Background:</b> Anxiety and depression symptoms are known to increase cancer symptom burden, yet little is known about the longitudinal integrations of these among Hispanic/Latinx patients. The goal of this study was to explore the trajectory and longitudinal interactions among anxiety and depression, cancer symptom burden, and health-related quality of life in Hispanic/Latinx cancer patients undergoing chemotherapy. Methods: Baseline behavioral assessments were performed before starting chemotherapy. Follow-up behavioral assessments were performed at 3, 6, and 9 months after starting chemotherapy. Descriptive statistics, chi-square tests, Fisher’s exact tests, and Mann–Whitney tests explored associations among outcome variables. Adjusted multilevel mixed-effects linear regression models were also used to evaluate the association between HADS scores, follow-up visits, FACT—G scale, MDASI scale, and sociodemographic variables. Results: Increased cancer symptom burden was significantly related to changes in anxiety symptoms’ scores (adjusted <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mover accent="true"><mi>β</mi><mo stretchy="false">^</mo></mover></semantics></math></inline-formula> = 0.11 [95% CI: 0.02, 0.19]. Increased quality of life was significantly associated with decreased depression and anxiety symptoms (adjusted <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mover accent="true"><mi>β</mi><mo stretchy="false">^</mo></mover></semantics></math></inline-formula> = −0.33; 95% CI: −0.47, −0.18, and 0.38 adjusted <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mover accent="true"><mi>β</mi><mo stretchy="false">^</mo></mover></semantics></math></inline-formula>= −0.38; 95% CI: −0.55, −0.20, respectively). Conclusions: Findings highlight the need to conduct periodic mental health screenings among cancer patients initiating cancer treatment.