Background: Perioperative mortality rate (POMR) has been identified as an important measure of access to safe surgical and anesthesia care in global surgery. There has been limited study on this measure in rural Ghana. In order to identify areas for future quality improvement efforts, we aimed to assess the epidemiology of exploratory laparotomy and to investigate POMR as a benchmark quality measure. Methods: Surgical records were reviewed at a regional referral hospital in Eastern Region, Ghana to identify cases of exploratory laparotomy from July 2017 through June 2018. Patient demographics, health information, and outcomes data were collected. Logistic regression was used to identify predictors of perioperative mortality. Findings: The study included operations for 286 adult and 60 pediatric patients. Only 60% of patients were covered by National Health Insurance (NHI). The overall POMR was 11.5% (12.6% adults; 6.7% pediatric). Sixty percent of mortalities were referrals from outside hospitals and the mortality rate for referrals was 13.5%. Odds of mortality was 13 times greater with perforated peptic ulcer disease (OR = 13.1, p = 0.025) and 12 times greater with trauma (OR = 11.7, p = 0.042) when compared to the most common operation. Female sex (OR = 0.3, p = 0.016) and NHI (OR = 0.4, p = 0.031) were protective variables. Individuals 60 years and older (OR = 3.3, p = 0.016) had higher mortality. Conclusion: POMR can be an important outcome and quality indicator for rural populations. Interventions aimed at decreasing emergent hernia repair, preventing perforation of peptic ulcer disease, improving rural infrastructure for response to major trauma, and increasing NHI coverage may improve POMR in rural Ghana.