PURPOSE Although cancer is an important and growing public health issue in Nepal, the country lacked any population-based cancer registry (PBCR) until 2018. In this study, we describe the establishment of the PBCR for the first time in Nepal and use the registry data to understand incidence, mortality, and patterns of cancer in the Kathmandu Valley (consisting of Kathmandu, Lalitpur, and Bhaktapur districts), which comprises 10.5% of the estimated 29 million population of Nepal in 2018. MATERIALS AND METHODS The PBCR collects information from facilities and communities through the active process. The facilities include cancer or general hospitals, pathology laboratories, hospice, and Ayurvedic centers. In the communities, the field enumerators or female community health volunteers collected the data from the households. In addition, the Social Security and Nursing Division under the Department of Health Services, which provides subsidy for cancer treatment of underprivileged patients, was another major source of data. The collected data were verified for residence, accuracy, and completeness and then entered and analyzed using CanReg5 software. RESULTS In the Kathmandu Valley, the PBCR registered 2,156 new cancer cases with overall age-adjusted incidence rate for all cancers of 95.7 per 100,000 population (95.3 for males and 98.1 for females). The age-adjusted mortality rate for males was 36.3 (n = 365) and for females 27.0 (n = 305) per 100,000 population. We found that the commonest cancers in males were lung and stomach, whereas in females, they were breast and lung cancer. Gallbladder cancer was among the top five common cancers in both sex. CONCLUSION These findings provide a milestone to understand the cancer burden in the country for the first time using the PBCR and will be helpful to develop and prioritize cancer control strategies.