Background: The landscape of treatment of patients with resectable stage III melanoma has evolved considerably given studies demonstrating survival benefit of anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy in the adjuvant setting, as well as surgical changes relating to the Multicenter Selective Lymphadenectomy Trial (MSLT)-II trial. Currently, the decision to treat with anti-PD-1 or BRAF/MEKi therapy in the adjuvant setting is dependent upon patient, provider, and institutional preferences, but no comparative analysis has been done between adjuvant therapy options. Methods: Clinical data from 141 surgically-resected staged III and oligometastatic stage IV patients receiving adjuvant anti-PD-1 (n = 66), BRAF/MEKi (n = 36), or surgery only (n = 39) between 2017 and 2021 was analyzed retrospectively. Primary endpoints were overall survival (OS) and progression free survival (PFS) between the three treatment groups. Secondary endpoints include the duration of adjuvant treatment and reasons for termination of therapy. Results: During a mean follow-up period of 17 months, 33.3% of anti-PD-1 patients and 16.7% of BRAF/MEKi patients experienced recurrence, while 41.0% of the surgery only patients experienced recurrence. In univariate Cox regression analyses of the survival data, patients who received anti-PD-1 (HR = 0.46, 95% CI: 0.25-0.87, p = 0.016) or BRAF/MEKi (HR = 0.44, 95% CI:0.21-0.90, p = 0.024) had significantly improved PFS compared to patients treated with surgery only, but the OS was not significantly different with treatment. A multivariate Cox regression model was performed, adjusting for age, sex, and melanoma disease stage. In this model, anti-PD-1 was still associated with improved PFS (HR = 0.33, p < 0.001), while BRAF/MEKi also trended towards improved PFS, but was not statistically significant (HR = 0.54, p = 0.13). Other associations include males having a significantly worse PFS (HR = 2.32, p = 0.009) and OS (HR = 5.86, p = 0.02), and patients with stage IIIC or worse disease having worse PFS (HR = 4.56, p < 0.001), but not significantly worse OS (HR = 4.84, p = 0.05). The average duration of adjuvant therapy was similar between both groups (250-260 days) with approximately half of the patients completing the treatment course. A larger proportion of BRAF/MEKi patients stopped treatment due to intolerable side effects compared to anti-PD-1 patients (83.3% vs. 64.0%). Conclusions: Adjuvant treatment decreases the chance of recurrence compared to surgery alone, but the benefit on overall survival is still inconclusive. Male and more advanced stage III melanoma prior to initiating adjuvant therapy are factors associated with an increased likelihood of recurrence. Although it appears that more patients terminated BRAF/MEKi therapy early due to side effects compared to anti-PD-1, additional follow-up will be needed to confirm this finding.