Inclusion Criteria:  Histologically or cytologically confirmed diagnosis of stage IV (metastatic) or recurrent or stage IIIc NSCLC (recurrent or stage IIIC NSCLC must be not a candidate for definitive multimodality therapy) Documented ALK re-arrangement as detected by: (1) fluorescence in situ hybridization (FISH), (2) immunohistochemistry (IHC), (3) tissue next generation sequencing (NGS), or (4) cell free deoxyribonucleic acid (cfDNA) NGS using Clinical Laboratory Improvement Amendments (CLIA) certified laboratory Subjects can be enrolled as (1) treatment naive (2) after progression on any number of prior ALK tyrosine kinase inhibitors (TKIs). Prior adjuvant platinum-based chemotherapy and platinum-based chemotherapy for metastatic disease is allowed if completed > 12 months from the study treatment start date with one exception: a patient may be eligible if started on chemotherapy while waiting for ALK testing results, provided no more than two cycles of chemotherapy were administered and no evidence of disease progression Life expectancy of at least 12 weeks Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Aged at least 18 years Brain metastases allowed if asymptomatic at study baseline. Patients must be not on steroids, with the maximum size of brain lesion not exceeding 30 millimeters. If patients have neurological symptoms or signs due to central nervous system (CNS) metastases, patients need to complete whole brain radiation or focal treatment at least 14 days before start of study treatment and be asymptomatic on stable or decreasing doses of corticosteroids at baseline Ability to swallow and retain oral medications Absolute neutrophil count (ANC) >= 1500/mm^3 /L Platelet count >= 100,000/mm^3 Hemoglobin (Hb) at least 9 g/dL (or 5.69 mmol/L) at baseline Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 60 mL/minute for subjects with creatinine levels > 1.5 x the institutional ULN Serum total bilirubin less than or equal to =< 1.5 x ULN or direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 x ULN Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN except for subjects with liver metastases (mets) for whom ALT and AST should be =< 5 x ULN International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants Activated PTT (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy if PT or PTT is within therapeutic range of intended use of anticoagulant Female patients of childbearing potential must have a negative pregnancy test documented at time of screening  Female patients who:  Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to use a highly effective method of contraception from the time of signing the informed consent through 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse  Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:  Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or Agree to completely abstain from heterosexual intercourse Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol  Exclusion Criteria:  Use of an investigational drug within 21 days prior to the first dose of study drug. Note that to be eligible, any drug-related toxicity should have recovered to grade 2 or less, with the exception of alopecia Major surgery within the last 4 weeks or radiotherapy within the last 14 days Patients with leptomeningeal disease are ineligible Patients with a previous malignancy within the past 2 years (other than curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, or any cancer that is considered to be cured and have no impact on PFS and overall survival [OS] for the current NSCLC) Concomitant systemic use of anticancer herbal medications. These should be stopped prior to study entry  Patients receiving:  Strong CYP3A inhibitors (including, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit, grapefruit juice) Strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort) CYP3A substrates with narrow therapeutic window (including, but not limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) Women who are pregnant or breastfeeding Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of study medications Patients at risk for GI perforation  Clinically significant cardiovascular disease including:  Corrected QT per Fridericia's formula (QTcF) interval > 450 ms for men and > 470 ms for women, symptomatic bradycardia < 45 beats per minute or other significant electrocardiogram (ECG) abnormalities in the investigator's opinion Clinically uncontrolled hypertension in the investigator's opinion (e.g., blood pressure > 160/100 mmHg; note that isolated elevated readings considered to not be indicative of uncontrolled hypertension are allowed)  The following within 6 months prior to cycle 1 day 1:  Congestive heart failure (New York Heart class III or IV) Arrhythmia or conduction abnormality requiring medication. Note: patients with atrial fibrillation/flutter controlled by medication and arrhythmias controlled by pacemakers are eligible Severe/unstable angina, coronary artery/peripheral bypass graft, or myocardial infarction Cerebrovascular accident or transient ischemia Patients who are immunosuppressed (including known human immunodeficiency virus [HIV] infection), have a serious active infection at the time of treatment, have interstitial lung disease/pneumonitis, or have any serious underlying medical condition that would impair the ability of the patient to receive protocol treatment. Patients with controlled hepatitis C, in the investigator's opinion, are allowed. Patients with known hepatitis B must be hepatitis B virus e antigen (HBeAg) and HB viral deoxyribonucleic acid (DNA) negative for enrollment. Note that, because of the high prevalence, all patients in the Asia-Pacific region (except Australia, New Zealand, and Japan) must be tested and, if hepatitis B surface antigen (HBsAg) positive, must be HBeAg and HB viral DNA negative for enrollment Known hypersensitivity to tartrazine, a dye used in the ensartinib 100 mg capsule Concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol or would impart excessive risk associated with study participation that would make it inappropriate for the patient to be enrolled Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol