Background: Distal tibialis anterior tendinopathy (DTAT) is a chronic condition that may lead to functional impairment and secondary forefoot deformities when left untreated. Current clinical practice is mainly guided by case reports and small retrospective case series; little consensus exists on which treatment protocol is most effective. This study aims to assess a conservative treatment for DTAT consisting of PRP infiltration and walking cast immobilization. Methods: This prospective study included 18 feet in 18 patients, recruited between September 2020 and September 2022 at a single institution. Ultrasonography was performed; leukocyte-poor PRP was infiltrated around the tibialis anterior tendon insertion. Walking cast immobilization was used for 3 weeks after infiltration, followed by eccentric exercises of the DTAT, and gastrocnemius-soleus muscle complex stretching. Clinical findings, visual analog scale (VAS), Foot Function Index (FFI), and American Orthopaedic Foot & Ankle Society (AOFAS) midfoot scores were recorded at inclusion, and 6 and 12 weeks after PRP infiltration. Minimal clinically important difference (MCID) limits were researched to assess clinical relevance of statistical outcomes. Means were determined for age, sex, and body mass index (BMI). One-way repeated measures ANOVA was performed over time for FFI, AOFAS, and VAS scores. Results: Mean age was 65 years with a mean BMI of 25. Tendon thickening and hypoechogenicity were the most commonly reported ultrasonographic findings. Significant improvement from baseline VAS (VASrest: 4.71 ± 2.7, VASactivity: 5.66 ± 2.5) to 12 weeks follow-up (VASrest: 2.14 ± 2.7, VASactivity: 3.34 ± 2.5) was found. Both AOFAS and FFITotal improved significantly from baseline (AOFAS: 66.9 ± 3.3, FFITotal: 32.9 ± 3.3) to 6-week follow-up (AOFAS6w: 79.4 ± 3.3, P = .019; FFITotal: 19.4 ± 3.3, P = .011). No statistically significant further improvement was found at 12 weeks compared to 6 weeks’ follow-up. Two (11%) patients chose operative treatment because of persisting symptoms. Conclusion: We found that PRP infiltration with walking cast immobilization as a first-line treatment was associated with general early symptom improvement. Level of Evidence: Level IV, case series.