Simple Summary: The spleen is an organ that can be affected by neoplastic and non-neoplastic lesions, which can induce diffuse, nodular, or multinodular organ growth. In dogs, few studies relate microscopical diagnosis of splenic lesions to tumor size and the number of nodules in spleen biopsies. Studying these potential associations could improve the diagnostic approach to these types of injuries, detected through several imaging techniques. This study aimed to characterize splenic masses and determine some risk factors for spleen tumors in dogs. The most frequent neoplastic and non-neoplastic diagnoses were hemangiosarcoma and hyperplasia, respectively. Most of the cases occurred in male, senior, and purebred individuals such as Cocker Spaniel, German Shepherd, and Labrador Retriever. It was determined that male sex, presence of two or more splenic nodules, and an increase in nodule size greater than 2 cm are risk factors for the presentation of splenic neoplasia, knowledge that can improve the diagnostic management of dogs with spleen lesions. In dogs, the spleen is a secondary lymphoid organ that can be affected by both neoplastic and non-neoplastic nodules. In general, few studies relate histopathological diagnosis to tumor size and the number of nodules in spleen biopsies. Some of these studies are inconclusive regarding the difference between neoplastic and non-neoplastic lesions and have small sample sizes or do not consider all splenic lesions. This study aimed to characterize splenic masses and determine risk factors for spleen tumors in dogs. A total of 507 histological reports corresponding to the diagnosis of splenic lesions in dogs from a private laboratory of animal pathology in the Metropolitan Region, Chile, were used. Data were analyzed by descriptive statistics and multiple logistic regression. The most frequent neoplastic and non-neoplastic diagnoses were hemangiosarcoma and hyperplasia, respectively. Most of the cases occurred in male (265 cases, 52.3%), senior (421 cases, 83%), and purebred individuals (342 cases, 67.5%). The most affected breeds were the Cocker Spaniel, German Shepherd, and Labrador Retriever. The most frequent lesion was a single nodule. The variables that exhibited a greater risk for the presentation of splenic neoplasia were male sex (odds ratio (OR) = 16.21; 95% confidence interval (CI) 1.741–150.879; p = 0.014), the presence of two or more splenic nodules (OR = 3.94; 95% CI 2.168–7.177; p < 0.001), an increase in nodule size greater than 2 cm (OR for quartiles 2, 3 and 4 of 2.2; 95% CI 1.036–4.941; p = 0.041, 2.9; 95% CI 1.331–6.576; p = 0.008, and 3.6; 95% CI 1.562–8.499; p = 0.003, respectively), and increasing age (OR = 1.23; 95% CI 1.048–1.436; p = 0.011). On the other hand, males exhibited a lower risk as age increases (OR = 0.76; 95% CI 0.615–0.928; p = 0.008). In conclusion, this study identified that males, multinodular presentation, nodule size, and age are risk factors for the occurrence of splenic neoplasia in dogs, knowledge that will contribute to the diagnostic management of dogs with spleen lesions. [ABSTRACT FROM AUTHOR]