Background The increasing trend of drugs and substances abuse (DSA) by different age groups and gender in parts of Kenya is not only a socio-economic problem but a public health concern. There is a need to determine prevalence, types and patterns of DSA by age and gender in order to develop all-inclusive and long-term strategies to prevent and manage the DSA within different communities. In this study we determined the prevalence of DSA, types and patterns of drugs and substances being abused and risk factors associated with this abuse. Methods A descriptive cross-sectional mixed methods study was conducted in four counties; Isiolo, Kajiado, Murang’a and Nyamira, all purposively selected from the 47 counties of Kenya based on the review reports of the Kenya Medical Research Institute’s County Cluster Coordinators which indicated that DSA was a priority health concern in the selected counties. From each county, two sub-locations each from two locations in one sub-county were purposively selected. In each sub-location, 225 households were systematically selected. Hence, a total of 3,600 participants were systematically sampled for quantitative data collection using an interviewer-based questionnaire to gather information on magnitude and causes of DSA. Additionally, in each county, qualitative data through in-depth interviews (IDIs) with 16 opinion leaders, 16 healthcare personnel, 16 previous DSAs, at least 5 county personnel, 32 current DSAs; and through 16 focus group discussions (FGDs) were concurrently collected to elicit more information on types, patterns and causes of DSA. The observed overall prevalence of DSA was calculated using binomial logistic regression model and factors associated with DSA analyzed using multilevel logistic regression model. Qualitative data was analyzed using QSR NVIVO version 10, thematically by types, patterns and causes of DSA by age and gender. Results Prevalence of DSA was 86.0% (95%CI: 84.9–87.2) with the highest prevalence being observed in Nyamira County, 89.8% (95%CI: 87.9–91.7). Age-wise, the highest prevalence was observed in persons aged between 45 to 53 years, 89.4% (95%CI: 86.9–92.0), followed by those aged 36 to 44 years, 88.0% (95%CI: 85.4–90.6). Majority of those who abuse drugs and substances were males; 94.5% (95%CI: 93.6–95.4). The most abused drugs or substances were packaged/legal alcohol at 25.2% (745), cigarettes 20.3% (600), local brew ( chang’aa) 16.3% (482), and khat ( miraa) 10.5% (311). Risk factors analysis revealed that DSA was significantly higher among males (adjusted odds ratio (aOR) = 7.02 (95%CI: 5.21–9.45), p<0.001), government employees (aOR = 2.27 (95%CI: 1.05–4.91), p = 0.036) and unmarried (aOR = 1.71 (95%CI: 1.06–2.77), p = 0.028). Conclusions These study findings are useful in informing development of specific control programmes which will address age, gender and county needs of DSA ...