Aim: Synthetic inorganic materials are commonly used as reinforcing agents in polyetheretherketone (PEEK) composite, whereas natural organic plant-based reinforcing agents are negligible. Surface hardness, roughness, and wettability are indicative factors of osseointegration behavior to be used as an implant material. This study evaluated micro surface hardness (MSH), nano surface hardness (NSH), surface roughness (SR), and contact angle (CA) of PEEK-Azadirachta indica reinforced at 10 wt%, 20 wt%, and 30 wt%. Settings and Design: This was an in vitro study. Materials and Methods: Neem (A. indica) leaf nanoparticles were prepared and reinforced with PEEK powder at 10%, 20%, and 30% weight ratios by injection molding. Sixty specimens underwent the microhardness and CA testing using a digital microhardness tester, and CA goniometer, respectively, and later nanoindentation test to analyze the nanohardness and SR. Statistical Analysis Used: A one-way ANOVA test with a 95% confidence interval for MSH and NSH, SR, and CA was performed on the samples. A post hoc Bonferroni test was conducted (α = 0.05) to compare the groups. Results: There was a significant increase in nanohardness (P = 0.000) with zero difference in microhardness (P = 0.514). The addition of 10 wt%, 20 wt%, and 30 wt% nanoparticles increased the SR value of the pure PEEK from 273.19 nm to 284.10 (3.99%), 296.91 (8.68%), and 287.54 (5.24%), respectively. In the analysis of the CA, CA 20% shows the lowest angle (63.69) with the highest for control specimens (82.39). There is an increase in the PEEK composite SR with a decrease in CA. Conclusions: The addition of plant-derived nanoparticles into the PEEK matrix has a significant impact on the hardness and hydrophobicity enhancing cell growth and osteoblastic differentiation during osseointegration of dental implants.