Aim and objective: To histologically compare alveolar bone repair after tooth extraction treated with melatonin and calcium sulfate in an in vivo experimental study in guinea pigs (Cavia porcellus). Materials and methods: The study was of longitudinal, prospective, and experimental design in an animal bio-model. A total of 24 male guinea pigs were included, weighing from 700 to 900 g and separated into two experimental groups (melatonin and calcium sulfate) for three periods (15, 30, and 45 days) at 15-day intervals after surgery. The guinea pigs were randomly included into groups for the time evaluated. Results: In relation to bone repair cells using calcium sulfate, the presence of osteoblasts at 15, 30, and 45 days was 39.0 ± 63, 55.3 ± 6.0, respectively, with 61.3 ± 10.0 cells per field. Regarding bone repair cells using melatonin, the presence of osteoblasts at 15, 30, and 45 days was 25.0 ± 3.7, 49.3 ± 1.5, respectively, with 53.6 ± 5.6 cells per field. Conclusion: Both melatonin and calcium sulfate were found to be useful in bone repair at a histological and clinical level, although they present certain nonsignificant, albeit marked advantages in the bone repair process when compared with the control socket at the histological level. Clinical significance: This research allows us to know the usefulness of these easily accessible chemicals for the generation of bone repair.