* Stage II-III colorectal cancer patients scheduled to receive oxaliplatin 510 mg/m\^2 (cumulative dose) over 12 weeks as a component of adjuvant leucovorin calcium (calcium folinate), 5-fluorouracil and oxaliplatin (FOLFOX) treatment, in which patients are scheduled to receive oxaliplatin 85 mg/m\^2 every 2 weeks for 12 weeks (i.e., 6 cycles), or adjuvant capecitabine and oxaliplatin (CAPOX) treatment, in which patients are scheduled to receive oxaliplatin 135 mg/m\^2 every 3 weeks for 12 weeks (i.e., 4 cycles)
* No prior neurotoxic chemotherapy
* No pre-existing clinical or pre-clinical peripheral neuropathy from any cause.
* No history of seizure disorder,
* No history of narrow-angle glaucoma.
* No symptoms of or history of schizophrenia, bipolar disease, suicidal thoughts and/or a major depression.
* No serious eating disorder such as bulimia or anorexia.
* No known diagnosis of ethanol (ETOH) addiction/dependence within the past 10 years.
* Concomitant medications:

* No concomitant use of other adjuvant pharmacologic interventions (e.g., gabapentin, pregabalin, venlafaxine) with known or hypothesized efficacy for peripheral neuropathy. Must be discontinued at least 7 days prior to start of protocol treatment
* No anticipated or concurrent use of any antidepressant or serotonin-altering agent known to interact with duloxetine, due to concern regarding cumulative toxicity and potential drug interactions.
* Use of a monoamine oxidase inhibitor (MAOI) or other antidepressants must be discontinued at least 14 days prior to start of protocol treatment.
* No concomitant treatment with strong CYP1A2 and CYP2D6 inhibitors.
* Chronic concomitant treatment with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants, phenothiazines, and Type 1C antiarrhythmics should be approached with caution. Concomitant administration of duloxetine and thioridazine should be avoided.
* No use of warfarin or heparin products.
* Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential, a negative pregnancy test done =\< 7 days prior to registration is required
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* In order to complete the mandatory patient-completed measure, patients must be able to speak and read English
* Calculated creatinine clearance \> 30 mL/min
* Aspartate aminotransferases (AST)/serum glutamic-oxaloacetic transaminase (SGOT) =\< 3 x upper limit of normal (ULN)