Cancer is one of the leading causes of death worldwide producing estimated cost of $161.2 billion in the US in 2017 only. Early detection of cancer would not only reduce cancer mortality rates but also dramatically reduce healthcare costs given that the 17 million new cancer cases in 2018 are estimated to grow 27.5 million new cases by 2040. Analytical devices based upon paper substrates could provide effective, rapid, and extremely low cost alternatives for early cancer detection compared to existing testing methods. However, low concentrations of biomarkers in body fluids as well as the possible association of any given biomarker with multiple diseases remain as one of the greatest challenges to widespread adoption of these paper-based devices. However, recent advances have opened the possibility of detecting multiple biomarkers within the same device, which could be predictive of a patient's condition with unprecedented cost-effectiveness. Accordingly, this review highlights the recent advancements in paper-based analytical devices with a multiplexing focus. The primary areas of interest include lateral flow assay and microfluidic paper-based assay formats, signal amplification approaches to enhance the sensitivity for a specific cancer type, along with current challenges and future outlook for the detection of multiple cancer biomarkers.