Background Despite the substantial reduction of under-five mortality (U5M) across the world, about 15,000 under-fives (U5s) die daily. Majority occurs in developing countries with Sub-Saharan African countries like Kenya accounting for over 50%. In Kenya, the former Nyanza Province in western region exhibits the highest U5MR of 82 deaths/1000 live births. Karemo Sub-County in Nyanza Province displays twice as much U5MR as Nyanza Province despite having relatively good access to private and public health facilities. Moreover, the influence of maternal risk factors on U5M remains unknown. Methodology: The current cross-sectional study assessed the influence of maternal risk factors associated with U5M in Karemo Sub-County in Siaya County in 299 households of women of reproductive age (15–49 years). Data was collected using pre-tested structured questionnaire on a face-to-face interview. Differences between proportions were determined using Chi-square test while binary logistic regression was used to determine the association between maternal factors and U5M. Results Results show that children of older mothers (35–49 years) had increased mortality relative to those of younger mothers (< 20 years) (OR = 2.484; 95%CI: 1.249–4.940; P = 0.009). Short preceding birth interval of (< 2 years) was associated with increased risk of U5M relative to longer preceding birth intervals (> 2 years) (OR = 2.079; 95%CI: 1.240–3.485; P = 0.005). Relative to primary education level, children born to mothers who had attained tertiary level had reduced risk of U5M (OR = 0.408; 95%CI: 0.208-0.800; P = 0.009). Higher birth orders of 4 and above were five times more associated withU5M compared to lower birth orders (OR = 5.442; 95%CI: 2.789–10.620; P < 0.0001). Polygamy was associated with increased risk of U5M (OR = 3.370; 95%CI: 1.922–5.910; P < 0.0001). Similarly, lower death rates of about 61% were observed among children of married mothers compared to those of single mothers (OR = 0.382; 95%CI: 0.218–0.669; P = 0.001). Employment, subsistent farmers and small-scale business mothers showed increased risk to U5M (OR = 3.505, 95%CI: 1.657–7.414; P = 0.001), 2.1 (OR = 2.196; 95%CI: 1.190–4.053; P = 0.012) and 5.6 (OR = 5.639; 95%CI: 2.871–11.077; P < 0.0001), respectively. Conclusion Strategies targeting promotion of girl-child education above primary levels, women economic empowerment and acceptance of family planning are considered fundamental interventions and should be emphasized in reducing U5M in this region.