Optical detection is one of the most used transduction methods in biosensors and apart from the commercially available instruments based on surface plasmon resonance (SPR), an emerging class of devices, based on both silica and plastic optical fibers (POFs), is finding its route. On the other hand, aptamers represent the next-generation biorecognition elements for biosensor implementation, thanks to several characteristics making them more appealing with respect to the conventional antibodies. The joint exploitation of plasmon resonance in plastic optical fibers and aptamers is here reported, focusing the attention on various relevant biological applications (e.g., thrombin, vascular endothelial growth factor (VEGF), and SARS-CoV-2 spike protein).