Background: Children and adolescents diagnosed with cancer, as well as their caregivers, often experience significant psychological distress, including anxiety, depression, and post-traumatic stress disorder (PTSD). Healthcare professionals (HCPs) face several challenges when providing services and support to this group. This study aimed to evaluate the prevalence of anxiety, depression, and PTSD among children and adolescents diagnosed with cancer and their caregivers, identify contributing factors, and measure progress over time. Additionally, it aimed to understand the experiences of Omani parents of children and adolescents diagnosed with cancer and explore the healthcare services and support provided from the perspectives of HCPs. Methods: A prospective cohort study was conducted from October 2021 to June 2023 among 92 Omani children and adolescents (aged 6–18 years) diagnosed with cancer and 92 their caregivers at three main oncology and hematology referral centers in Oman. Validated Arabic-language versions of the Screen for Child Anxiety-Related Disorders and the Center for Epidemiologic Studies Depression Scale for Children were employed to assess anxiety and depression, respectively, among the children and adolescents diagnosed with cancer. The validated Arabic-language versions of the State-Trait Anxiety Inventory and the Center for Epidemiologic Studies Depression Scale were used to assess anxiety and depression among the caregivers. The validated Arabic-language versions of the Impact of Event Scale-Revised was utilized to measure PTSD. An initial assessment (T1) was conducted within the first three months of diagnosis, followed by a second assessment (T2) 3–6 months later. Additionally, two qualitative studies were conducted from December 2021 to December 2023 among 20 parents of children and adolescents with cancer and 22 HCPs at pediatric referral oncology and hematology centers in Oman. Semi-structured interviews were used to collect data. Statistical analysis was performed using SPSS Statistics Software for Windows, version 23, to analyze the quantitative data, while the framework analysis using NVivo-14 was employed to analyze the qualitative data. Result: The prevalence rates of anxiety, depression, and PTSD in children and adolescents were 43.5%, 56.5%, and 32.6%, respectively, at T1 and decreased to 38.0%, 35.9%, and 23.9%, respectively, at T2. The prevalence rates of state anxiety, trait anxiety, depression, and PTSD among caregivers were 45.7%, 53.3%, 45.7%, and 68.5%, respectively, at T1 and decreased to 32.6%, 42.4%, 33.7%, and 55.4%, respectively, at T2. At T1, the results showed a significant increase in anxiety, depression, and PTSD scores as the child’s age increased (p = 0.005, 0.001, and 0.001, respectively). Adolescents showed a significant increase in anxiety, depression, and PTSD scores compared to children (p = 0.041, 0.012, and 0.001, respectively). Children and adolescents aware of their cancer diagnosis showed significant increases in both anxiety and PTSD scores (p = 0.003, and 0.004, respectively). Patients identified as having a high risk of cancer exhibited significantly increased PTSD scores (p = 0.001). Similarly, at T2, there were significant increases in anxiety, depression, and PTSD scores as the child’s age increased (p 0.001). Adolescents showed greater anxiety, depression, and PTSD scores compared to children (p = 0.006, 0.001, and 0.002, respectively). Children and adolescents aware of their cancer diagnosis showed significant increases in anxiety, depression, and PTSD scores (p = 0.007, 0.003, and 0.005, respectively). Patients identified as having a high risk of cancer exhibited significantly increased anxiety and depression scores (p = 0.007). Additionally, at T1, depression scores among caregivers increased as the child's age decreased (p = 0.002), with caregivers of adolescents experiencing more depression than those of younger children (p = 0.004). Caregivers of children unaware of their cancer diagnosis had higher depression scores (p 0.001). Female caregivers had higher anxiety and depression scores than male caregivers (p = 0.007 and 0.001, respectively), with mothers showing higher depression scores (p = 0.029). At T2, depression scores were higher for caregivers of female children (p = 0.037). Caregivers of children had higher PTSD scores than those of adolescents (p = 0.041). Caregivers of children treated with chemotherapy and transplant had higher anxiety, depression, and PTSD scores (p = 0.021, 0.044, and 0.004, respectively). Anxiety scores decreased as caregiver age increased (p = 0.032). The qualitative study with parents identified five main themes: (1) The journey to diagnosis, including the benign phase, medical experiences, and emotional impact; (2) Living with the child’s diagnosis, covering daily life impact, burden, oncology center experiences, and coping strategies; (3) Cultural aspects of cancer, such as community beliefs and cultural terminology; (4) Impact of cancer on the child, including emotional, physical, and social effects; and (5) Child’s adaptation to cancer, including medical care and social support. The qualitative study with HCPs identified six main themes: (1) Medical care services for children and adolescents, including diagnostic, therapeutic, and supportive services; (2) Medical care services for caregivers, including therapeutic and social services; (3) The impact of caring for children and adolescents with cancer on HCPs, including psychological effects and intrinsic rewards; (4) Challenges facing medical care services, such as resource insufficiency and adolescent care challenges; (5) Psychological support provided by HCPs, including support extent, referrals, and barriers; and (6) Challenges facing psychological care services, including societal and cultural barriers, lack of psychological services, and the psychological impact of transitioning adolescents to adult services. Conclusion: Omani children and adolescents recently diagnosed with cancer, along with their caregivers, exhibit high levels of anxiety, depression, and PTSD. Cancer significantly impacts their psychological, physiological, social, and financial well-being. Age-appropriate communication, ongoing support, and mental health services are recommended to help this patient group cope and manage their emotional health. Additional psychological support, such as counseling for caregivers, is essential to reduce distress and address potential mental health challenges. Healthcare professionals at the oncology center in Oman face various challenges that need to be addressed. Psychological interventions are crucial for managing well-being, and future research should evaluate their effectiveness in reducing these disorders.