Few studies have reported vaccine effectiveness (VE) and population-level impact of the 13-valent pneumococcal conjugate vaccination (PCV13) among children with immunocompromising or chronic medical conditions putting them at risk of developing pneumococcal disease. The objective of this systematic literature review (SLR) was to summarize the efficacy, effectiveness, and impact of PCV13 in the prevention of invasive pneumococcal disease (IPD) and all-cause pneumonia among children with risk conditions. Peer-reviewed studies published between January 2000 and July 2024 were identified in MEDLINE, Embase, CENTRAL, and CDSR. Of 3008 records identified, full texts of 189 studies (6.3%) were reviewed and 11 (0.4%) studies evaluating PCV13 alone or in combination with PCV7 were included. Vaccine effectiveness or impact of PCV13 was reported in children with sickle cell disease (SCD; n = 2), HIV (n = 4), post-transplant conditions (n = 1), cancer (n = 1), combined immunocompromising conditions (n = 1), combined chronic medical and immunocompromising conditions (n = 1), and congenital heart disease (n = 1). In children with immunocompromising conditions, VE against PCV13-type IPD ranged between 83.8% and 91%. Compared to the pre-PCV era, the introduction of PCV13 in pediatric immunization programs was associated with a relative reduction of IPD due to any serotype between 86% and 100% in children SCD and 55% to 80% in children with cancer. PCV impact, as measured by incidence rate reductions, among children with HIV varied by comparison period, age group and outcome and ranged from 9.1% to 81% for any IPD. These findings support PCV vaccination for children with risk conditions although evidence was limited and heterogeneous.