Current electrochemical sensors in point-of-care (POC) testing devices rely mainly on enzyme-based sensors owing to superior sensitivity and selectivity. Nevertheless, the poor stability, high reagent cost, complex fabrication methods and requirement of specific operational conditions make their adaptability in real-world applications unfavorable. Non-enzymatic electrochemical sensors are thus developed as they are more robust and cost-effective strategies. The advancement in material science and nanotechnology enables the development of novel non-enzymatic electrodes with favorable analytical performance. However, the developments are yet far from being adopted as viable products. This review therefore aims to gain insight into the field and evaluate the current progress and challenges to eventually propose future research directions. Here, fabrication strategies based on traditional and emerging technology are discussed in the light of analytical performance and cost-effectiveness. Moreover, the discussion is given on the pros and cons of non-enzymatic sensors when they are employed with various kinds of sample matrices, i.e., clinical and non-clinical samples, which must be taken into consideration for sensor development. Furthermore, molecular imprinting technology in tackling the selectivity issue is introduced and current progress is provided. Finally, the promising strategies from literature for solving the remaining challenges are included which could facilitate further development of robust POC testing devices based non-enzymatic sensors. We believe that once researchers and technology developers have reached the point where most problems are solved, the non-enzymatic sensors are going to be the robust choice for POC testing in clinical diagnostic, ensuring food safety, monitoring contaminants in environment, and bioprocess control.