Being one of the four primary characters, Toothy has interacted with every other character in the series except for Lammy and Mr. Pickels. Toothy has been known to act friendly towards everyone he meets, even more so than other characters.
- Main article: Toothy-Cuddles Relationship
Toothy and Cuddles are best friends, as shown in various episodes. The things they did together include teasing zoo animals in From A to Zoo, dressing in costumes in Autopsy Turvy, and throwing snowballs in Strain Kringle. A particular sign of their friendship stands out in Blast from the Past as Cuddles consoles an injured Toothy. Even at the one time they weren't in good terms, they came to forgive each other in the end.
Giggles is also one of Toothy's friends. In Blast from the Past, she and Cuddles consoled Toothy after he broke his arm in the playground. Toothy was happy to see Giggles being put down by Splendid in Better Off Bread. He was also mad at Splendid for hurting Giggles in See What Develops. Cuddles is often seen with them, which would make sense considering he is their friend and also Giggles' main love interest.
For the most part, Lumpy and Toothy are friends. However, there are moments where their friendship is tested, such as We're Scrooged!, in which Lumpy deliberately kills Toothy before selling his body parts as toys for profit. He also captured Toothy (along with several other characters) and cracked his head like an egg in Dunce Upon a Time.
Petunia and Toothy are most likely friends. Their main interaction involved them building a snowman together in From Hero to Eternity. They have also been on trips together on several occasions, including Happy Trails Pt. 1, From A to Zoo, Take a Hike, and Camp Pokeneyeout.
Despite being in the same place a few times, they haven't quite met each other yet. The closest thing of an interaction between them so far would be Breaking Wind, where a dead Handy accidentally crashed his tow trunk into Toothy, and in Class Act Handy is clearly awed by Toothy's singing.
Nutty and Toothy are usually friends, going on various trips together and acting in a school play. However, like many characters, he has been a victim of Nutty's candy addiction. This is demonstrated in Chew Said a Mouthful as Nutty kidnaps Toothy in the midst of a surgery and kills him in pursuit of a jawbreaker.
- Main article: Toothy-Sniffles Relationship
Similar to Cuddles, Sniffles can be considered as one of Toothy's closest friends. They appear together in moments such as Ski Kringle, Ipso Fatso, A Sight for Sore Eyes, and Camp Pokeneyeout. They are usually seen with Cuddles; Toothy possibly being the glue who holds the trio together.
His main interaction with them occurred in Read 'em and Weep, where Pop and Cub attended Toothy's yard sale and bought one of his books. Pop accidentally killed Toothy and several others in And the Kitchen Sink while attempting to save Cub.
Toothy and Flaky are friends. They have been on trips in several episodes, acted in a school play in Class Act, celebrated Flippy's birthday party in Party Animal, attended a cruise in Snow Place to Go, and played along with Petunia and Flippy in Hide and Seek.
Toothy and The Mole worked as firefighters together in Who's to Flame?. It is likely that The Mole had Toothy as a customer in Wipe Out! and was awed by his singing in Class Act. Though in Spare Tire, Toothy was understandably horrified after The Mole drove through his house.
Who's to Flame?, Toothy and Disco Bear were seen as co-workers in a fire brigade. In Cubtron Z Toothy and Disco Bear can be seem together along with Mime.
Lifty and Shifty have taken advantage of Toothy once in Junk in the Trunk. He simply acted puzzled after Shifty tapped his shoulder, not suspecting they would steal his pet tortoise. They also appeared at a dinner party together sitting opposite each other in Kringle Feast, implying somewhat of a friendship.
Toothy and Mime can be considered friends despite rarely meeting each other. Toothy gets along very well with Mime. In Mime and Mime Again Mime visits Toothy in the hospital when he is injured and tries to entertain him with tricks, they both work together in Mime to Five, and in A Change of Heart they are both seen waiting in line together. They also went to see a movie together in YouTube Copyright School, along with Sniffles.
- Main article: Splendid-Toothy Relationship
Toothy appears to be a big fan of Splendid, from dressing up like the superhero in Remains to be Seen to attending his speech in Wrath of Con. The only exception would be in See What Develops, where Toothy gets mad at Splendid for mistakenly beating up Giggles.An Inconvenient Tooth. The picture sits next to picture with Cuddles and Giggles. Considering how Toothy is best friends with both Cuddles and Giggles, it is possible that Toothy and Truffles are good friends as well.