Histology is a preclinical subject transversal in medical, dental, and veterinary curricula. Classical teaching approaches in histology are often undermined by lower motivation and engagement of students, which may be addressed by innovative learning environments. Herein, we developed a serious game approach and compared it with a classical teaching style. The students' feedback was evaluated by questionnaires, and their performance on quizzes and exam's scores were assessed. The serious game (Histopoly) consisted of a game-based web application for the teacher/game master, a digital gaming application used by the students as a controller, and a projected digital board game. The board featured rows for the four fundamental tissues (epithelial, connective, muscular, and nervous) paired with question tiles and additional tiles with more demanding activities (e.g., drawing, presenting slides, and making a syllabus). Participants included all veterinary students enrolled in the first year. Paired laboratory sessions were split with four sections (n = 94 students) playing Histopoly at the end of all sessions and two sections (n = 28 students) completing small evaluations every three weeks at the beginning of sessions. According to the questionnaires, students that played the serious game were more motivated, engaged, and more interconnected with classmates. The activity was considered fun, and students enjoyed the classes more. No differences in the final examination scores were found, but the percentage of correct answers provided throughout the serious game was significantly higher. Overall, these findings argue for the inclusion of serious games in modern histology teaching to promote student engagement in learning.