Background: Anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients. The study aimed to explore the efficacy and safety of anlotinib combined with carboplatin and pemetrexed followed by anlotinib combined with pemetrexed maintenance in advanced EGFR/ALK wild-type non-squamous non-small-cell lung cancer (nsq-NSCLC). Methods: This multicenter (n = 6), single-arm clinical trial recruited patients with wild-type EGFR/ALK advanced nsq-NSCLC who received first-line therapy between March 2019 and February 2021. Patients received anlotinib (12 mg p.o., QD d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m, iv, d1, Q3W) + carboplatin (AUC = 5, iv, d1, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints are OS, objective response (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Feb 2021, 44 patients were enrolled and 38 of them have received at least one tumor assessment. The median age was 62 (range: 33-75) years. Most of the patients were non-smoker (68.4%). The median follow-up was 13.6 (range: 12.3-14.9) months. Median PFS was 10.5 (95%CI: 4.1, 17.0) months, and median OS was 23.4 (95%CI: NE, NE) months. The DCR and ORR were 94.7% and 60.5%, respectively. Twelve participants had treatment-related adverse events (TEAEs) of grade > 3. The most common Grade 3 AEs were hypertension (23.7%), neutropenia (19.4%), and bone marrow hypocellular (10.5%). Seven patients discontinued treatment, including two during induction and five during maintenance. No grade 5 TRAE was recorded. In the non-smoker participants, the median PFS was 14.5 (95%CI: 4.0-25.0) months. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin followed by anlotinib plus pemetrexed maintenance therapy might be a promising treatment for patients with wild-type EGFR/ALK advanced nsq-NSCLC. The combination was well tolerated, and the AEs were manageable. Clinical trial information: NCT03790228.